Novel n- and c-terminal substituted antagonistic analogs of gh-rh

ABSTRACT

There is provided a novel series of synthetic analogs of hGH-RH(1-29)NH 2  (SEQ ID NO: 1) and hGH-RH(1-30)NH 2 . Of particular interest are those carrying PhAc, N-Me-Aib, Dca, Ac-Ada, Fer, Ac-Amc, Me-NH-Sub, PhAc-Ada, Ac-Ada-D-Phe, Ac-Ada-Phe, Dca-Ada, Dca-Amc, Nac-Ada, Ada-Ada, or CH 3 —(CH 2 ) 10 —CO-Ada, at the N-Terminus and β-Ala, Amc, Apa, Ada, AE 2 A, AE 4 P, ε-Lys(α-NH 2 ), Agm, Lys(Oct) or Ahx, at the C-terminus. These analogs inhibit the release of growth hormone from the pituitary in mammals as well as inhibit the proliferation of human cancers, and inhibit the hyperplastic and benign proliferative disorders of various organs, through a direct effect on the cancerous and non-malignant cells. The stronger inhibitory potencies of the new analogs, as compared to previously described ones, result from replacement of various amino acids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/183,715, filed on Feb. 19, 2014, which is a continuation of U.S.application Ser. No. 12/890,626 filed on Sep. 25, 2010, now issued asU.S. Pat. No. 8,691,942, which is continuation-in-part of PCTApplication No. US2009/038351 filed on Mar. 26, 2009, which claims thebenefit of U.S. Provisional Application No. 61/040,418 filed on Mar. 28,2008. U.S. application Ser. No. 12/890,626 also claims the benefit ofU.S. Provisional Application No. 61/305,737 filed on Feb. 18, 2010. Allof the prior applications are incorporated herein by reference in theirentirety.

GOVERNMENT INTERESTS

This invention was made in part with Government support from the MedicalResearch Service of the Veterans Affairs Department. The Government hascertain rights in this application.

INCORPORATION OF SEQUENCE LISTING

A computer readable form of the sequence listing “12-890626 SequenceListing_ST25.txt” (743 bytes) submitted via EFS-WEB and created on Oct.17, 2013, is herein submitted.

FIELD OF INVENTION

The present invention relates to novel Synthetic analogs ofhGH-RH(1-29)NH₂ and hGH-RH(1-30)NH₂ that inhibit the release of growthhormone from the pituitary in mammals as well as inhibit theproliferation of human cancers, and inhibit the hyperplastic and benignproliferative disorders of various organs, through a direct effect onthe cancerous and non-malignant cells, and to therapeutic compositionscontaining these novel peptides.

BACKGROUND OF THE INVENTION

Growth hormone-releasing hormone (GH-RH) is a peptide belonging to thesecretin/glucagon family of neuroendocrine and gastrointestinalhormones, a family that also includes vasoactive intestinal peptide(VIP), pituitary adenylate cyclase activating peptide (PACAP) andothers. Human GH-RH (hGH-RH) peptide is comprised of 44 amino acidresidues. The best known site of production of GH-RH is thehypothalamus, but it was found that various peripheral organs alsosynthesize it. hGH-RH is also produced, sometimes in large quantities,by human malignant tissues (cancers) of diverse origin.

GH-RH exerts various physiological and pathophysiological functions.Hypothalamic GH-RH is an endocrine releasing hormone that, actingthrough specific GH-RH receptors on the pituitary, regulates thesecretion of pituitary growth hormone (GH). The physiological functionsof GH-RH in extrapituitary tissues are less clear. However, there isincreasing evidence for the role of GH-RH as an autocrine/paracrinegrowth factor in various cancers. Splice variant (SV) receptors forGH-RH, different from those expressed in the pituitary, have beendescribed in a wide range of human cancers and in some normal peripheralorgans. The actions of tumoral autocrine/paracrine GH-RH could beexerted on these receptors. In addition, receptors for VIP and other, asyet unidentified receptors of this family, could all be targets of localGH-RH.

In view of the role of GH-RH as an endocrine regulator of GH release,novel therapeutic strategies, based on the use of agonistic andantagonistic analogs of GH-RH, have been devised for the treatment ofvarious pathological conditions.

GH is a polypeptide having 191 amino acids that stimulates theproduction of different growth factors, e.g. insulin-like growth factorI (IGF-I), and consequently promotes growth of numerous tissues(skeleton, connective tissue, muscle and viscera) and stimulates variousphysiological activities (raising the synthesis of nucleic acids andproteins, and raising lipolysis, but lowering urea secretion). Releaseof pituitary GH is under the control of releasing and inhibiting factorssecreted by the hypothalamus, the primary releasing factors being GH-RHand ghrelin, and the main inhibiting factor being somatostatin.

GH has been implicated in several diseases. One disease in which GH isinvolved is acromegaly, in which excessive levels of GH are present. Theabnormally enlarged facial and extremity bones, and the cardiovascularsymptoms of this disease can be treated by administering a GH-RHantagonist. Further diseases involving GH are diabetic retinopathy anddiabetic nephropathy. The damage to the retina and kidneys respectivelyin these diseases, believed to be due to hypersecretion of GH, resultsin blindness or reduction in kidney function. This damage can beprevented or slowed by administration of an effective GH-RH antagonist.

In an effort to intervene in these disease and other conditions, someinvestigators have attempted to control GH and IGF-I levels by usinganalogs of somatostatin, an inhibitor of GH release. However,somatostatin analogs, if administered alone, do not suppress GH or IGF-Ilevels to a desired degree. If administered in combination with a GH-RHantagonist, somatostatin analogs will suppress IGF-I levels much better.

However, the main applications of GH-RH antagonists are in the field ofcancer (reviewed in Schally A V and Varga J L, Trends Endocrinol Metab10: 383-391, 1999; Schally A V et al, Frontiers Neuroendocrinol 22:248-291, 2001; Schally A V and Comaru-Schally A M, in: Kufe D W, PollockR E, Weichselbaum R R, Bast Jr. R C, Gansler T S, Holland J F, Frei IIIE, Eds. Cancer Medicine, 6^(th) ed. Hamilton, Ontario: BC. Decker, Inc.,2003, p. 911-926). GH-RH antagonists inhibit the proliferation ofmalignancies by indirect endocrine mechanisms based on the inhibition ofpituitary GH release and resulting in the decrease of serum levels of GHand IGF-I, as well as by direct effects on the tumor tissue.

GH-RH and its tumoral splice variant (SV) receptors are present in humancancers of the lung, prostate, breast, ovary, endometrium, stomach,intestine, pancreas, kidney, and bone (see Halmos G et al, Proc NatlAcad Sci USA 97: 10555-10560, 2000; Rekasi Z et al, Proc Natl Acad SciUSA 97: 10561-10566, 2000; Schally A V et al, Frontiers Neuroendocrinol22: 248-291, 2001; Schally A V and Comaru-Schally A M, in: Kufe D W,Pollock R E, Weichselbaum R R, Bast Jr. R C, Gansler T S, Holland J F,Frei III E, Eds. Cancer Medicine, 6^(th) ed. Hamilton, Ontario: BC.Decker, Inc., 2003, p. 911-926). Tumoral GH-RH has been shown or it issuspected to act as an autocrine growth factor in these malignancies.Antagonistic analogs of GH-RH can inhibit the stimulatory activity ofGH-RH and exert direct antiproliferative effects in vitro on cancercells, and in vivo on tumors. Direct antiproliferative effects of GH-RHantagonists are exerted on tumoral receptors (binding sites). Inaddition to the specific tumoral SV receptors for GH-RH, receptors forVIP and other, as yet unidentified receptors of this family, are targetsof GH-RH antagonists.

In addition to endocrine inhibitory effects on serum GH and IGF-I, GH-RHantagonists have been found to reduce the autocrine and paracrineproduction of several tumor growth factors and/or downregulate theirreceptors. These growth factors include IGF-I, IGF-II, GH, vascularendothelial growth factor (VEGF), and fibroblast growth factor (FGF),Thus, a disruption of the autocrine/paracrine stimulatory loops based onthese growth factors contributes to the efficacy of GH-RH antagonists asantitumor agents.

IGF-I and IGF-II are autocrine/paracrine growth factors with potentmitogenic effects on various cancers. IGF-I is also an endocrine growthfactor, and elevated levels of serum IGF-I are considered anepidemiological risk factor for the development of prostate cancer, lungcancer, and colorectal cancer. The involvement of IGF-I (somatomedin-C)in breast cancer, prostate cancer, colon cancer, bone tumors and othermalignancies is well established. Nevertheless, autocrine/paracrinecontrol of proliferation by IGF-II is also a major factor in manytumors. IGF-I and IGF-II exert their proliferative and anti-apoptoticeffects through the common IGF-I receptor. The receptors for IGF-I arepresent in primary human breast cancers, prostate cancers, lung cancers,colon cancers, brain tumors, pancreatic cancers, and in renal cellcarcinomas. In several experimental cancers, such as those of the bone,lung, prostate, kidney, breast, ovary, intestine, pancreas, and brain,treatment with GH-RH antagonists produces a reduction in IGF-I and/orIGF-II levels, concomitant to inhibition of tumor growth (reviewed inSchally A V and Varga J L, Trends Endocrinol Metab 10: 383-391, 1999;Schally A V et al, Frontiers Neuroendocrinol 22: 248-291, 2001; SchallyA V and Comaru-Schally A M, in: Kufe D W, Pollock R E, Weichselbaum R R,Bast Jr. R C, Gansler T S, Holland J F, Frei III E, Eds. CancerMedicine, 6^(th) ed. Hamilton, Ontario: BC. Decker, Inc., 2003, p.911-926). In some cases, the expression of IGF-I receptors was alsodecreased by GH-RH antagonists. Thus the disruption of endocrine andautocrine/paracrine stimulatory loops dependent on IGF-I and IGF-IIcontributes to the antitumor effect of GH-RH antagonists.

In MXT breast cancer model, treatment with GH-RH antagonists inhibitedtumor growth, reduced the mRNA level for GH and the concentration of GHpeptide in tumors, and inhibited the mRNA expression for GH receptors(Szepeshazi K et al, Endocrinology 142: 4371-4378, 2001). GH was shownto act as a growth factor for MXT murine mammary carcinoma cells, MCF-7human breast cancer cells and other tumor cell lines. Thus theinhibitory activity of GH-RH antagonists on local and serum GH levelscontributes to their antitumor effect.

GH-RH antagonists have been shown to inhibit the mRNA levels and proteinconcentrations of VEGF in human androgen-sensitive andandrogen-independent prostate cancer models (Letsch M et al, Proc NatlAcad Sci USA 100: 1250-1255, 2003; Plonowski A et al, Prostate 52:173-182, 2002) and this phenomenon contributes to their antitumoreffect, since VEGF plays an important stimulatory role in theneovascularization and growth of various tumors. Moreover, it was foundthat a GH-RH antagonist inhibited the VEGF secretion and proliferationof normal murine endothelial cells, apparently through a direct effecton these cells in vitro (Siejka A et al, Life Sci 72: 2473-2479, 2003).

Scientists have investigated various modifications of GH-RH to elucidatethe relationship of the structure of GH-RH to its activity on thepituitary receptors, in an effort to provide synthetic congeners withimproved agonistic or antagonistic properties. Thus, it was earlyestablished that GH-RH fragment comprising residues 1 to 29, orGH-RH(1-29), is the minimum sequence necessary for biological activityon the pituitary. This fragment retains 50% or more of the potency ofnative GH-RH. Subsequently, many synthetic analogs of GH-RH, based onthe structure of hGH-RH(1-29)NH₂ (SEQ ID NO: 1) peptide, were prepared.hGH-RH(1-29)NH₂ (SEQ ID NO: 1) has the following amino acid sequence:

(SEQ ID NO: 1) Tyr-Ala-Asp-Ala-Ile⁵-Phe-Thr-Asn-Ser-Tyr¹⁰-Arg-Lys-Val-Leu-Gly¹⁵-Gln-Leu-Ser-Ala-Arg²⁰-Lys-Leu-Leu-Gln-Asp²⁵-Ile-Met-Ser-Arg²⁹-NH₂ 

A considerable number of patents and articles in the open literaturedisclose analogs of GH-RH which either act as agonists of GH-RH (i.e.act to stimulate the release of GH) or as antagonists of GH-RH (i.e. actto inhibit the release of GH) on the pituitary. Most of these peptidesare derived from the GH-RH(1-29) peptide sequence, with specificstructural modifications which account for their enhanced agonistic orantagonistic properties on the pituitary receptors. However, apart froma few exceptions, it is not known how these analogs would behave oncancer cells that express GH-RH receptors different from those found inthe pituitary. Only a few published scientific studies tried toelucidate the structure-activity relationships and characterize thedirect antagonistic (or agonistic) effects of GH-RH analogs on cancercells and tumors (see Rekasi Z et al, Endocrinology 141: 2120-2128,2000; Halmos G et al, Proc Natl Acad Sci USA 97: 10555-10560, 2000;Rekasi Z et al, Proc Natl Acad Sci USA 97: 10561-10566, 2000; Kiaris Het al, Proc Natl Acad Sci USA 99: 196-200, 2002), and no issued patentshave dealt with this issue so far. Consequently, very little is knownabout the structural features in GH-RH analogs required for a directantagonistic action on tumor cells.

The first described GH-RH antagonist, [Ac-Tyr¹, D-Arg²]hGH-RH(1-29)NH₂,which is generally termed as the “standard antagonist” in theliterature, was found to prevent the activation of rat anteriorpituitary adenylate cyclase by hGH-RH(1-29)NH₂ (SEQ ID NO: 1). The samepeptide blocked the action of GH-RH on its receptors in the pituitaryand hypothalamus, and inhibited the pulsatile growth hormone secretion.The standard antagonist was also evaluated clinically (Ocampo-Lim B etal, J Clin Endocrinol Metab 81: 4396-4399, 1996; Jaffe C A et al, J ClinEndocrinol Metab 82: 634-637, 1997). Large doses of this antagonist (400μg/kg) eliminated nocturnal GH secretion in normal subjects andinhibited the response to GH-RH. The standard GH-RH antagonist alsoreduced GH levels in a patient with acromegaly. However, for clinicaluse, much more potent antagonists of GH-RH are required.

The inventions mentioned below disclose GH-RH analogs with antagonisticor agonistic properties on the pituitary receptors for GH-RH. However itwas not reported and not investigated whether these analogs could exertdirect effects on tumor cells. U.S. Pat. No. 4,659,693 discloses GH-RHantagonistic analogs which contain certain N,N¹-dialkyl-omega-guanidinoalpha-amino acyl residues in position 2 of the GH-RH(1-29) sequence.Published application WO 91/16923 reviews earlier attempts to alter thesecondary structure of hGH-RH by modifying its amino acid sequence.These earlier attempts include: replacing Tyr¹, Ala², Asp³ or Asn⁸ withtheir D-isomers; replacing Asn⁸ with L- or D-Ser, D-Arg, Asn, Thr, Glnor D-Lys; replacing Ser⁹ with Ala to enhance amphiphilicity of theregion; and replacing Gly¹⁵ with Ala or Aib. When R² in the analogs isD-Arg, and R⁸, R⁹, and R¹⁵ are substituted as indicated above,antagonistic activity is said to result. These antagonistic peptides aresaid to be suitable for administration as pharmaceutical compositions totreat conditions associated with excessive levels of GH, e.g.,acromegaly.

The antagonistic activity of the hGH-RH analogue“[Ser⁹-psi[CH₂—NH]-Tyr¹⁰]hGH-RH(1-29)” of U.S. Pat. No. 5,084,555 wassaid to result from the pseudopeptide bond (i.e., a peptide bond reducedto a [CH₂—NH] linkage) between the R⁹ and R¹⁰ residues. However, theantagonistic properties of [Ser⁹-psi[CH₂—NH]-Tyr¹⁰]hGH-RH(1-29) weresaid to be inferior to the standard antagonist, [Ac-Tyr¹,D-Arg²]hGH-RH(1-29)-NH₂. U.S. Pat. No. 5,550,212, U.S. Pat. No.5,942,489, and U.S. Pat. No. 6,057,422, disclose analogs ofhGH-RH(1-29)NH₂ (SEQ ID NO: 1) said to have enhanced antagonisticproperties and prolonged duration of action regarding the inhibition ofGH-RH-evoked GH release. These properties are believed to result fromreplacement of various amino acids and acylation with aromatic ornonpolar acids at the N-terminus of GH-RH(1-29)NH₂. The tumor inhibitoryproperties of antagonists featured in U.S. Pat. No. 5,942,489 and U.S.Pat. No. 6,057,422 have been demonstrated by using nude mice bearingxenografts of experimental human cancer models. It is noted that in U.S.Pat. No. 5,550,212, and in U.S. Pat. No. 5,942,489, R⁹ is always Ser,while R¹¹ and R²⁰ can be either Arg, D-Arg, or Cit. In the case of U.S.Pat. No. 6,057,422, R⁹ can be either Arg, Har, Lys, Orn, D-Arg, D-Har,D-Lys, D-Orn, Cit, Nle, Tyr(Me), Ser, Ala, or Aib, while R¹¹ and R²⁰ arealways Arg.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a plot of tumor growth in % against time in days of the effectof certain novel GHRH antagonists on PC3 androgen-independent prostatecancer.

FIG. 2 is a plot of tumor growth in % against time in days of the effectof certain novel GHRH antagonists on human non-small cell lung cancercell line H-460.

SUMMARY OF THE INVENTION

There is provided a novel series of synthetic analogs of hGH-RH(1-29)NH₂(SEQ ID NO: 1) and hGH-RH(1-30)NH₂. These analogs inhibit the release ofgrowth hormone from the pituitary in mammals as well as inhibit theproliferation of human cancers, and inhibit the hyperplastic and benignproliferative disorders of various organs, through a direct effect onthe cancerous and non-malignant cells. The stronger inhibitory potenciesof the new analogs, as compared to previously described ones, resultsfrom replacement of various amino acids.

The invention principally relates to peptides comprising the formulae: Apeptide selected from the group having the formulae:

[A⁰-Tyr¹-D-Arg²,A⁴,A⁶,A⁸,Har⁹,Tyr(Me)¹⁰,A¹¹,A¹²,Abu¹⁵,A¹⁷,A²⁰,A²¹,Nle²⁷,D-Arg²⁸,A²⁹-A³⁰-A³¹]hGH-RH(1-29)NH₂

wherein

A⁰ is PhAc, N-Me-Aib, Dca, Ac-Ada, Fer, Ac-Amc, Me-NH-Sub, PhAc-Ada,Ac-Ada-D-Phe, Ac-Ada-Phe, Dca-Ada, Dca-Amc, Nac-Ada, Ada-Ada, orCH₃—(CH₂)₁₀—CO-Ada,

A⁴ is Ala or Me-Ala

A⁶ is Cpa or Phe(F)₅

A⁸ is Ala, Pal, or Me-Ala

A¹¹ is His or Arg

A¹² is Lys, Lys(0-11), Lys(Me)₂ or Orn,

A¹⁷ is Leu or Glu

A²⁰ is Har or His

A²¹ is -Lys, Lys(Me)₂ or Orn

A²⁹ is Har, Arg or Agm

A³⁰ is absent, β-Ala, Amc, Apa, Ada, AE₂A, AE₄P, ε-Lys(α-NH₂) or Agm

A³¹ is absent, Lys(Oct) or Ahx

provided that where A⁰ is PhAc, A¹² and A²¹ are both other than Orn andA³⁰ is not absent, and

[A⁰-Tyr¹,D-Arg²,Cpa⁶,Ala⁸,His⁹,Tyr(Et)¹⁰,His¹¹,Orn¹²,Abu¹⁵,His²⁰,Orn²¹,Nle²⁷,D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂

wherein A⁰ is Oct or Ac-Ada,

and pharmaceutically acceptable salts thereof.

The invention principally relates to peptides comprising the formulae: Apeptide selected from the group having the formulae:

[A⁰-Tyr¹,D-Arg²,A⁴,A⁶,A⁸,Har⁹,A¹⁰,A¹¹,A¹²,A¹⁵,A¹⁷,A²⁰,A²¹,Nle²⁷,D-Arg²⁸,A²⁹-A³⁰-A³¹]hGH-RH(1-29)NH₂

whereinA⁰ is PhAc, Nac, Oct, N-Me-Aib, Dca, Ac-Ada, Fer, Ac-Amc, Me-NH-Sub,PhAc-Ada, Ac-Ada-D-Phe, Ac-Ada-Phe, Dca-Ada, Dca-Amc, Nac-Ada, Ada-Ada,or CH₃—(CH₂)₁₀—CO-Ada,

A⁴ is Ala or Me-Ala

A⁶ is Cpa or Phe(F)₅

A⁸ is Ala, Pal, Dip, or Me-Ala

A¹⁰ is Tyr (Alk) where Alk is Me or Et,

A¹¹ is His or Arg

A¹² is Lys, Lys(0-11), Lys(Me)₂ or Orn,

A¹⁵ is Abu or Orn, A¹⁷ is Leu or Glu A²⁰ is Har or His

A²¹ is -Lys, Lys(Me)₂ or Orn

A²⁹ is Har, Arg or Agm

A³⁰ is absent, β-Ala, Amc, Apa, Ada, AE₂A, AE₄P, ε-Lys(α-NH₂) or AgmA³¹ is absent, Lys(Oct) or Ahxprovided that where A⁰ is PhAc, Nac, or Oct, A³⁰ is not absent,and pharmaceutically acceptable salts thereof.

Suitably, [A⁰-Tyr¹, D-Arg², Ala⁴, A⁶, A⁸, Har⁹, A¹⁰, His¹¹, A¹², Abu¹⁵,A¹⁷, His²⁰, A²¹, Nle²⁷, D-Arg²⁸, Har²⁹-A³⁰]hGH-RH(1-29)NH₂

whereinA⁰ is PhAc, Dca, Ac-Ada, Fer, Ac-Amc, PhAc-Ada, Ac-Ada-D-Phe, Dca-Ada,Dca-Amc, Nac, Oct, or CH₃—(CH₂)₁₀—CO-AdaA⁶ is Cpa or Phe(F)₅

A⁸ is Ala or Me-Ala

A¹⁰ is Tyr (Alk) where Alk is Me or Et

A¹² is Lys, or Orn, A¹⁷ is Leu or Glu A²¹ is -Lys, or Orn

A³⁰ is absent, Amc, Apa, Ada, AE₂A, or Agmprovided that where A⁰ is PhAc, Nac, or Oct, A³⁰ is not absentand pharmaceutically acceptable salts thereof.

Most suitably, peptides listed in the immediately foregoing paragraphwherein A⁰ is Dca, Ac-Ada, Ac-Amc, PhAc-Ada, Dca-Ada, Nac, Oct, orCH₃—(CH₂)₁₀—CO-Ada and A³⁰ is Agm, Ada, or absent.

It is noted that the amino acid residues from 30 through 44 of thenative GH-RH molecule do not appear to be essential to activity; nordoes their identity appear to be critical. Therefore, it appears thatthe addition of some or all of these further amino acid residues to theC-terminus of the hGH-RH(1-29)NH₂ (SEQ ID NO: 1) and hGH-RH(1-30)NH₂analogs of the present invention will not affect the efficacy of theseanalogs as GH-RH antagonists.

If some or all of these amino acids were added to the C-terminus of thehGH-RH(1-29)NH₂ (SEQ ID NO: 1) analogs, the added amino acid residuescould be the same as residues 30 through 44 in the native hGH-RHsequence or reasonable equivalents.

Synthetic Methods.

The synthetic peptides are synthesized by a suitable method such as byexclusive solid phase techniques, by partial solid-phase techniques, byfragment condensation or by classical solution phase synthesis. When theanalogs of this invention are synthesized by solid-phase method, theC-terminus residue (here, A²⁹ or A³⁰) is appropriately linked (anchored)to an inert solid support (resin) while bearing protecting groups forits alpha or omega amino group (and, where appropriate, for its sidechain functional group). After completion of this step, the alpha (oromega) amino protecting group is removed from the anchored amino acidresidue and the next amino acid residue, A²⁸ or A²⁹ respectively, isadded having its alpha amino group (as well as any appropriate sidechain functional group) suitably protected, and so forth. The N-terminusprotecting groups are removed after each residue is added, but the sidechain protecting groups are not yet removed. After all the desired aminoacids have been linked in the proper sequence, the peptide is cleavedfrom the support and freed from all side chain protecting group(s) underconditions that are minimally destructive towards residues in thesequence. This is be followed by a careful purification and scrupulouscharacterization of the synthetic product, so as to ensure that thedesired structure is indeed the one obtained.

It is particularly preferred to protect the alpha amino function (or theomega amino function, where applicable) of the amino acids during thecoupling step with an acid or base sensitive protecting group. Suchprotecting groups should have the properties of being stable in theconditions of peptide linkage formation, while being readily removablewithout destruction of the growing peptide chain and withoutracemization of any of the chiral centers contained therein. Suitablealpha and omega amino protecting groups are Boc and Fmoc.

Medical Applications

The hGH-RH antagonist peptides, or salts of these peptides, may beformulated in pharmaceutical dosage forms containing effective amountsthereof and administered to humans or animals for therapeutic ordiagnostic purposes. The peptides may be used to suppress GH levels andto treat conditions associated with excessive levels of GH, e.g.,diabetic retinopathy and nephropathy, and acromegaly. Also provided aremethods for treating these diseases by administration of a compositionof the invention to an individual needing such treatment. The main usesof GH-RH antagonists are, however, in the field of cancer, for examplehuman cancers of the lung, prostate, breast, ovary, endometrium,stomach, colon, pancreas, kidney, bone, and brain where the receptorsfor GH-RH, IGF-I/IGF-II, or GH are present, and that depend onstimulation by growth factors such as GH-RH, IGF-I, IGF-II, GH, VEGF, orFGF.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A. Abbreviations

The nomenclature used to define the peptides is that specified by theIUPAC-IUB Commission on Biochemical Nomenclature wherein, in accordancewith conventional representation, the amino group at the N-terminusappears to the left and the carboxyl group at the C-terminus appears tothe right. The term “natural amino acid” as used herein means one of thecommon, naturally occurring L-amino acids found in naturally occurringproteins: Gly, Ala, Val, Leu, Ile, Ser, Thr, Lys, Arg, Asp, Asn, Glu,Gln, Cys, Met, Phe, Tyr, Pro, Trp and His. When the natural amino acidresidue has isomeric forms, it is the L-form of the amino acid that isrepresented herein unless otherwise expressly indicated.

Non-coded amino acids, or amino acid analogues, are also incorporatedinto the GH-RH antagonists. (“Non-coded” amino acids are those aminoacids which are not among the approximately 20 natural amino acids foundin naturally occurring proteins.) When these non-coded amino acids, oramino acid analogues, have isomeric forms, it is the L-form of the aminoacid that is represented unless otherwise expressly indicated.

Abbreviations used herein are:

-   Abu alpha-aminobutyric acid-   Ac acetyl-   AcOH acetic acid-   Ac₂O acetic anhydride-   Ada 12-aminododecanoyl-   AE₂A 8-amino-3,6-dioxaoctanoyl-   AE₄P 15-amino-4,7,10,13-tetraoxapentadecanoyl-   Agm agmatine-   Ahx 6-Aminohexanoyl-   Amc 8-Aminocaprylyl-   Apa 5-Aminopentanoyl-   Aib alpha-aminoisobutyroyl-   All allyl-   Alloc allyloxycarbonyl-   Amp para-amidino-phenylalanine-   Bpa para-benzoyl-phenylalanine-   Boc tert-butyloxycarbonyl-   Bom benzyloxymethyl-   2BrZ 2-bromo-benzyloxycarbonyl-   Bzl benzyl-   Cha cyclohexylalanine-   Chg cyclohexylglycine-   cHx cyclohexyl-   Cit citrulline (2-amino-5-ureidovaleroyl-   2ClZ 2-chloro-benzyloxycarbonyl-   Cpa para-chlorophenylalanine-   Dat des-amino-tyrosine-   Dca Dichloroacetyl-   DCM dichloromethane-   DIC N,N¹-diisopropylcarbodiimide-   DIEA diisopropylethylamine-   Dip (3,3-diphenyl)alanine-   DMF dimethylformamide-   Et ethyl-   Fer ferulyl-   FGF fibroblast growth factor-   Fm fluorenylmethyl-   Fmoc fluorenylmethoxycarbonyl-   For formyl-   GH growth hormone-   GH-RH GH releasing hormone-   Gup para-guanidino-phenylalanine-   Har homoarginine-   HBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-Tetramethyluronium    hexaflourophosphate-   Hca hydrocinnamoyl-   Hca-OH hydrocinnamic acid-   hGH-RH human GH-RH-   HOBt 1-hydroxybenzotriazole-   HPLC high performance liquid chromatography-   lbu isobutyryl-   lndAc indole-3-acetyl-   lpa indole-3-propionyl-   Lys(0-11) Lys(A⁰-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-)-   ε-Lys(α-NH₂) a Lys residue, the ε-amino group of which is acylated    by the carbonyl group of an N-terminally located amino acid; the    α-amino group of the Lys residue is free para-methylbenzhydrylamine-   MBHA para-methylbenzhydrylamine-   Me methyl-   MeOH methanol-   MeCN acetonitrile-   Nac naphthylacetyl-   Nal naphthylalanine-   Nle norleucine-   NMM N-methylmorpholine-   Npr naphthylpropionyl-   Oct octanoyl-   Orn ornithine-   Peg pegyl-   Pal pyridylalanine-   PAM phenylacetamidomethyl-   Ph Phenyl-   PhAc phenylacetyl-   PhAc-OH Phenylacetyl-   Phe(F)₅ pentafluoro-phenylalanine-   Phe(pCI) para-chloro-phenylalanine-   Phe(pNH₂) para-amino-phenylalanine-   Phe(pNO₂) para-nitro-phenylalanine-   rGH-RH rat GH-RH-   RP-HPLC reversed phase HPLC-   Sub suberyl-   SPA para-sulfonyl-phenoxyacetyl-   TFA trifluoroacetic acid-   Tos para-toluenesulfonyl-   Tpi 1,2,3,4-tetrahydronorharman-3-carboxylic acid-   Tyr(Me) O-methyl-tyrosine-   Tyr(Et) O-ethyl-tyrosine-   z benzyloxycarbonyl

B. The GH-RH Analogs

The hGH-RH analogs of the present invention were designed to increasethe antagonistic effects at the pituitary level, and/or at the tumorallevel.

Particularly preferred are the peptides of the structure shown in TableA below:

TABLE A P-1109  [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, Glu¹⁷, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-1111 [PhAc⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-1113  [PhAc⁰-Tyr¹,D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-1115  [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-1117  [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, (Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11107 [(N-Me-Aib)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11111 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂P-11113 [Fer⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11115 [(Ac-Amc)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11117 [(PhAc-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11119 [(Ac-Ada-D-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11121 [(Ac-Ada-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11123 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11125 [(CH₃-(CH₂)₁₀-CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11207 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂ P-11209[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹-Apa³⁰]hGH-RH(1-29)NH₂ P-11211 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11213 [Oct⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,His⁹, Tyr(Et)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂ P-11215 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11307 [(Ac-Amc)-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1- 29)NH₂ P-11309 [(Me-NH-Sub)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1- 29)NH₂ P-11311 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Agm²⁹]hGH-RH(1-29) P-11313 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Agm³⁰]hGH-RH(1- 29) P-11315 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11317 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11319 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,His⁹, Tyr(Et)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11321 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11407 [(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH- RH(1-29)NH₂ P-11408 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11409 [(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH- RH(1-29)NH₂ P-11411 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂ P-11413 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, 3-Pal⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂ P-11415 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Agm³⁰]hGH-RH(1-29) P-11417 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1- 29)NH₂ P-11419 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-AE₂A]hGH-RH(1- 29)NH₂ P-11421 [(N-Me-Aib)-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH- RH(1-29)NH₂ P-11423 [PhAc-Tyr¹, D-Arg², Cpa⁶,Dip⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1- 29)NH₂ P-11425 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0- 11)¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂, where (0-11) denotes thefollowing peptide sequence:PhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His-; and theC-terminal carbonyl group of the (0-11) peptide sequence forms an amidebond with the epsilon amino group of Lys¹² P-11427 [(N-Me-Aib)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0-11)¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂; where (0-11) denotes thefollowing peptide sequence:(N-Me-Aib)-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala- Har-Tyr(Me)-His-; theC-terminal carbonyl group of the (0- 11) peptide sequence forms an amidebond with the epsilon amino group of Lys¹² P-11429 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-β-Ala³⁰-Lys(Oct)³¹] hGH-RH(1-29)NH₂ P-11431[(N-Me-Aib)-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-β-Ala³⁰- Lys(Oct)³¹]hGH-RH(1-29)NH₂ P-11433 [Nac⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1- 29)NH₂ P-11435 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1- 29)NH₂ P-11437 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1- 29)NH₂ P-11439 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, (Lys(Me)₂)₂₁, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1- 29)NH₂ P-11441 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, (Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11443 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂ P-11445 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, (Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11447 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Har²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11449 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Har²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂ P-11451 [(Nac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH- RH(1-29)NH₂ P-11453 [(Dca-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH- RH(1-29)NH₂ P-11455 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH- RH(1-29)NH₂ P-11457 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂ P-11459 [(PhAc⁰-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂ P-11461 [(Ac-Ada-Phe)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ P-11463 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂ P-11465 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11467 [(Ada-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11469 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11471 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0-11)¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ where (0-11) denotes thefollowing peptide sequence: PhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His-; and the C-terminal carbonyl group of the (0-11) peptidesequence forms an amide bond with the epsilon amino group of Lys¹²P-11473 [(PhAc⁰-Ada)-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂P-11475 [(Ac-Ada-D-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11477 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹³, Glu¹⁷, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29) NH₂ P-11479 [(Ac-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ P-11481 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-ε-Lys(α- NH₂)³⁰-Ahx³¹]hGH-RH(1-29)NH₂ P-11483[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH- RH(1-29)NH₂P-11485 [(CH₃-(CH₂)₁₀CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11487 [(CH₃-(CH₂)₁₀CO-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11491 [(Dca-Ada)⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ P-11497 [(Ac-Amc)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11499 [PhAc⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11501 [(Ac-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹-β-Ala³⁰- Lys(Oct)³¹]hGH-RH(1-29)NH₂ P-11503[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂ P-11513 [Dca⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Har²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11515 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0-11)¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ where (0-11) denotes the followingpeptide sequence: PhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His-; and the C-terminal carbonyl group of the (0-11) peptidesequence forms an amide bond with the epsilon amino group of Lys¹²P-11521 [(Dca-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Orn¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂P-11523 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Orn¹⁵, Glu¹⁷, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂P-11525 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Orn¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂P-11601 [(CH₃-(CH₂)₁₀-CO-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11602 [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ P-11603 [(Dca-Ada)⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11604 [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹, Agm³⁰] hGH-RH(1-29) P-11606 [(PhAc⁰-Ada)-Tyr¹, D-Arg²,(Phe(F)₅)⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹², Orn¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹, Agm³⁰]hGH-RH(1-29) P-11610 PhAc⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, (Phe(F)₅)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂ P-11611[(Ac-Amc)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹- Ada³⁰]hGH-RH(1-29)NH₂ P-11612 [(Ac-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11620 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11621 [(Me-NH-Sub)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂ P-11630 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1- 29)NH₂ P-11701 [(Dca-Ada)-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Glu¹⁷, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH- RH(1-29)NH₂ P-11702 [(Dca-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Glu¹⁷, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹- AE₄P³⁰]hGH-RH(1-29)NH₂ P-11703 [(Dca-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Glu¹⁷, Har²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹- AE₄P³⁰]hGH-RH(1-29)NH₂ P-11704[(CH₃-(CH₂)₁₀-CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂

Especially preferred are peptides having the formula shown in Table Bbelow:

TABLE B P-1109  [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, Glu¹⁷, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11109[Dca⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11111 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11113 [Fer⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂P-11115 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11117[(PhAc-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11119[(Ac-Ada-D-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11123[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11125[(CH₃—(CH₂)₁₀—CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ P-11209[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹-Apa³⁰]hGH-RH(1-29)NH₂ P-11213 [Oct⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, His⁹, Tyr(Et)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂ P-11307 [(Ac-Amc)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1- 29)NH₂ P-11313 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Agm³⁰]hGH-RH(1- 29) P-11317 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11408 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11433 [Nac⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-AE₂A³⁰] hGH-RH(1- 29)NH₂ P-11435 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂ P-11457 [PhAc-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂ P-11459 [(PhAc-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂ P-11469 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11473 [(PhAc-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11479 [(Ac-Ada)⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ P-11485[(CH₃—(CH₂)₁₀CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂P-11491 [(Dca-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11497 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11499 [PhAc⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11521 [(Dca-Amc)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Orn¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11601[(CH₃—(CH₂)₁₀—CO-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂P-11602 [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11604 [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹², Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹,Agm³⁰] hGH-RH(1-29) P-11606 [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹, Agm³⁰]hGH-RH(1-29) P-11610 PhAc⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, (Phe(F)₅)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1- 29) NH₂ P-11612 [(Ac-Ada)⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰] hGH-RH(1-29)NH₂

Most preferred are peptides having the formula shown in Table C below:

TABLE C P-11109 [Dca⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11113 [Fer⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11117 [(PhAc-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11119 [(Ac-Ada-D-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11123 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂ P-11125 [(CH₃—(CH₂)₁₀—CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11213 [Oct⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, His⁹, Tyr(Et)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11307 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1- 29)NH₂P-11313 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Agm³⁰]hGH-RH(1- 29) P-11317[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ P-11408[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11433 [Nac⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰] hGH-RH(1- 29)NH₂ P-11435 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂ P-11457 [PhAc-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂ P-11459 [(PhAc-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1- 29)NH₂ P-11469 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11473 [(PhAc-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH- RH(1-29)NH₂ P-11485[(CH₃—(CH₂)₁₀CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂P-11491 [(Dca-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11601 [(CH₃—(CH₂)₁₀—CO-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ P-11602 [(PhAc-Ada)⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH- RH(1-29)NH₂ P-11604 [(PhAc-Ada)⁰-Tyr¹,D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹, Agm³⁰] hGH-RH(1-29) P-11606[(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹,Agm³⁰]hGH-RH(1-29) P-11610 PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,(Phe(F)₅)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1- 29)NH₂

C. Method of Preparation Overview of Synthesis

The peptides are synthesized by suitable methods such as by exclusivesolid phase techniques, by partial solid-phase techniques, by fragmentcondensation or by classical solution phase synthesis. For example, thetechniques of exclusive solid-phase synthesis are set forth in thetextbook “Solid Phase Peptide Synthesis”, J. M. Stewart and J. D. Young,Pierce Chem. Company, Rockford, Ill., 1984 (2nd. ed.), and M. Bodanszky,“Principles of Peptide Synthesis”, Springer Verlag, 1984. The hGH-RHantagonist peptides are preferably prepared using solid phase synthesis,such as that generally described by Merrifield, J. Am. Chem. Soc., 85 p.2149 (1963), although other equivalent chemical syntheses known in theart can also be used as previously mentioned.

The synthesis is carried out with amino acids that are protected attheir alpha amino group. Urethane type protecting groups (Boc or Fmoc)are preferably used for the protection of the alpha amino group. Incertain cases, protected omega-amino acids are also used during thesynthesis. Boc and Fmoc protecting groups are also appropriate for theprotection of omega-amino groups.

In solid phase synthesis, the N-alpha-protected or N-omega-protectedamino acid moiety which forms the aminoacyl group of the final peptideat the C-terminus is attached to a polymeric resin support via achemical link. After completion of the coupling reaction, the alpha (oromega) amino protecting group is selectively removed to allow subsequentcoupling reactions to take place at the amino-terminus, preferably with50% TFA in DCM when the N-alpha-(N-omega-) protecting group is Boc, orby 20% piperidine in DMF when the N-alpha-(N-omega-) protecting group isFmoc. The remaining amino acids with similarly Boc or Fmoc-protectedalpha (or omega) amino groups are coupled stepwise to the free aminogroup of the preceding amino acid on the resin to obtain the desiredpeptide sequence. Because the amino acid residues are coupled to thealpha (or omega) amino group of the C-terminus residue, growth of thesynthetic hGH-RH analogue peptides begins at the C terminus andprogresses toward the N-terminus. When the desired sequence has beenobtained, the peptide is acylated at the N-terminus, and it is removedfrom the support polymer.

Each protected amino acid is used in excess (2.5 or 3 equivalents) andthe coupling reactions are usually carried out in DCM, DMF or mixturesthereof. The extent of completion of the coupling reaction is monitoredat each stage by the ninhydrin reaction. In cases where incompletecoupling is determined, the coupling procedure is repeated, or a cappingby acetylation of unreacted amino groups is carried out, before removalof the alpha (or omega) amino protecting group prior to the coupling ofthe next amino acid.

Typical synthesis cycles are shown in Table I and Table II.

TABLE I Protocol for a Typical Synthetic Cycle Using Boc-strategy MixingStep Reagent Time (min) 1. Deprotection 50% TFA in DCM  5 + 25 DCM wash1 2-propanol wash 1 2. Neutralization 5% DIEA in DCM 1 DCM wash 1 MeOHwash 1 5% DIEA in DCM 3 MeOH wash 1 DCM wash (3 times) 1 3. Coupling 3eq. Boc-amino acid in DCM or 60  DMF + 3 eq. DIC or the preformed HOBtester of the Boc-amino acid MeOH wash (3 times) 1 DCM wash (3 times) 14. Acetylation Ac₂0 in pyridine (30%) 10 + 20 (if appropriate) MeOH wash(3 times) 1 DCM wash (3 times) 1

TABLE II Protocol for a Typical Synthetic Cycle Using Fmoc-strategyMixing Step Reagent Time (min) 1. Deprotection 20% piperidine in DMF 5 +15 DMF wash (3 times) 1 2. Coupling 3 eq. Fmoc-amino acid in DMF + 60 3eq. DIC or + 3 eq. HBTU + 3 eq. HOBt + 6 eq. DIEA DMF wash (3 times) 13. Acetylation 3 eq. 1-acetylimidazole in DMF 30 (if appropriate) DMFwash (3 times) 1

After completion of the synthesis, the cleavage of the peptide from theresin can be effected using procedures well known in peptide chemistry.

2. Choice of the Support Polymer.

The hGH-RH antagonist peptides may be synthesized on a variety ofsupport polymers, i.e. MBHA, Merrifield, PAM, Rink amide or Wang resins.The peptides can also be synthesized on aminomethyl, MBHA, or otherresins that have been previously derivatized with suitable linkers.Examples of such linkers are the base-labile 4-hydroxymethyl benzoicacid (HMBA) linker for the attachment of C-terminal carboxyl groups orthe acid-labile para-sulfonyl-phenoxyacetyl (SPA) linker which permitsthe attachment of agmatine through its guanidino group.

When peptides with an amidated C-terminus are synthesized by using Bocstrategy, the preferred resin is MBHA. Attachment of the C-terminalamino acid to this resin can be accomplished by the standardDIC-mediated coupling method described in Table I.

In order to prepare peptides with a C-terminal ethylamide (—NHEt)modification, the Merrifield resin or HMBA-MBHA resin can be used inconjunction with the Boc strategy. Loading of the C-terminal amino acidonto the Merrifield resin is done by coupling mediated by potassiumfluoride (KF) or cesium salt at elevated temperature.

For the synthesis of peptides having Agm at the C-terminus, it ispreferred that the support phase is MBHA resin or an aminomethyl resin.The guanidino group of Boc-Agm is joined to the support polymer througha stable, but readily cleavable linker such as thepara-sulfonyl-phenoxyacetyl (SPA) moiety. The alpha-amino-Boc-protectedAgm is reacted with the chlorosulfonyl phenoxyacetic acidCI—SO₂—C₆H₄—O—CH₂—COOH to form Boc-Agm-SO₂—C₆H₄—O—CH₂—COOH. Thiscompound is then coupled to the support polymer e.g. to MBHA resin usingDIC or HBTU-HOBt-DIEA as activating reagent to yield Boc-Agm-SPA-MBHA.

3. Amino Acid Derivatives Used.

Bifunctional amino acids, i.e. those not having side chain functionalgroups, are mostly used in the form of their N-alpha Boc- orFmoc-derivatives for synthesis. Bifunctional omega-amino acids are alsotypically used in the form of their N-omega Boc- or Fmoc-derivatives.Thus, Boc-Gly-OH or Fmoc-Gly-OH is typically used for incorporating theGly residue. The naturally occurring bifunctional amino acids are Gly,Ala, Val, Leu, Ile, Phe, and Pro, and some well-known non-codedbifunctional amino acids used in this invention are Abu, Aib, and Nle.

Some of the amino acid residues of the peptides have side chainfunctional groups which are reactive with reagents used in coupling ordeprotection. When such side chain groups are present, suitableprotecting groups are joined to these functional groups to preventundesirable chemical reactions occurring during the reactions used toform the peptides. The following general rules are followed in selectinga particular side chain protecting group: (a) the protecting grouppreferably retains its protecting properties and is not split off undercoupling conditions, (b) the protecting group should be stable underconditions for removing the alpha amino protecting group at each step ofthe synthesis, (c) the side chain protecting group must be removableupon the completion of the synthesis of the desired amino acid sequence,under reaction conditions that will not undesirably alter the peptidechain.

When Boc-amino acids are used in the synthesis, the reactive side chainfunctional groups can be protected as follows: Tos or nitro (NO₂) forArg and Har; cHx or Fm for Asp and Glu; Bom for His; 2CIZ or Fmoc forLys and Orn; Bzl for Ser and Thr; For for Trp; and 2BrZ for Tyr. Theside chains of Asn and Gin are unprotected. In the case of Fmocsynthesis, the reactive side chain functional groups can be protected byother appropriate protective groups as follows:2,2,4,6,7-pentamethyl-dihydrobenzofurane-5-sulfonyl (Pbf) or bis-Boc forArg and Har; tert-butyl (tBu) for Asp and Glu; no protective group ortrityl (Trt) protection for Asn and Gin; Trt for His; Boc or4-methoxytrityl (Mmt) for Lys and Orn; tBu or Trt for Ser and Thr; Bocfor Trp; and tBu or 2-chlorotrityl (2CITrt) for Tyr.

In addition to the widely known coded and non-coded amino acidsmentioned above, some of the peptides of this application contain lesscommon non-coded amino acids such as homoarginine (Har); ornithine(Orn); O-methyl-tyrosine [Tyr(Me)]; pentafluoro-phenylalanine [Phe(F)₅];para-amidino-phenylalanine (Amp); para-guanidino-phenylalanine (Gup);cyclohexylalanine (Cha); 1,2,3,4-tetrahydronorharman-3-carboxylic acid(Tpi); (2-naphthyl)alanine (2-Nal); (3,3-diphenyl)alanine (Dip);para-amino-phenylalanine [Phe(pNH₂)]; para-nitro-phenylalanine[Phe(pNO₂)]; (3-pyridyl)alanine (3-Pal); O-ethyl-tyrosine [Tyr(Et)]; andpara-benzoyl-phenylalanine (Bpa). These amino acid residues areincorporated into the peptides by coupling the suitable protected aminoacid derivatives. A non-exclusive list of such protected amino acidderivatives that can be used is as follows: Boc-Amp(Alloc)-OH,Boc-Amp-OH, Fmoc-Amp(Alloc)-OH, Fmoc-Amp-OH, Boc-Gup(Tos)-OH,Boc-Gup-OH, Fmoc-Gup(Boc)₂-OH, Fmoc-Gup-OH, Boc-Cha-OH, Boc-Tpi-OH,Boc-2-Nal-OH, Boc-Dip-OH, Boc-Phe(pNH—Z)—OH, Boc-Phe(pNO₂)—OH,Boc-3-Pal-OH, Boc-Tyr(Et)-OH, Boc-Tyr(Me)-OH, Boc-Phe(F)₅—OH, andBoc-Bpa-OH. The protected derivatives of noncoded amino acids mentionedabove are commonly available from several commercial suppliers,including Bachem (King of Prussia, Pa.), Peptides International(Louisville, Ky.), Novabiochem (San Diego, Calif.), Advanced ChemTech(Louisville, Ky.), and RSP Amino Acid Analogues DBA (Worcester, Mass.),and AnaSpec (San Jose, Calif.).

4. Stepwise Coupling of Amino Acid Residues

Utilizing the above mentioned support polymers and after loading of theC-terminal amino acid or Agm residue, the peptide itself may suitably bebuilt up by solid phase synthesis in the conventional manner. Eachprotected amino acid is coupled in about a three-fold molar excess, withrespect to resin-bound free amino residues, and the coupling may becarried out in a medium such as DMF-DCM (1:1) or in DMF or DCM alone.The selection of an appropriate coupling reagent is within the skill ofthe art. Particularly suitable as coupling reagents are N,N′-diisopropylcarbodiimide (DIC), or HBTU combined with HOBt in the presence of DlEA.The success of the coupling reaction at each stage of the synthesis ispreferably monitored by the ninhydrin reaction. In cases whereincomplete coupling occurs, either the coupling procedure is repeated,or the resin-bound unreacted amino residues are acetylated using acapping reagent, before removal of the alpha (or omega) amino protectinggroup. Suitable capping reagents are 1-acetylimidazole andAc₂O-pyridine.

Final acylation of the N-terminus of the peptide with monocarboxylicacids is done in the same way as the previous couplings, with thedifference that the appropriate carboxylic acid is used instead of anamino acid. When dicarboxylic acids are attached to the N-terminus andit is desired that only one —COOH group reacts with the amino terminusof the peptide (that is, monoamides of these acids are prepared), theanhydrides of the respective dicarboxylic acids can be used forcoupling. The cyclic anhydrides of many dicarboxylic acids arecommercially available; in other cases the pre-formed anhydrides ofthese acids are prepared by treatment with DIC and used for coupling.

5. Cleavage of the Peptide from the Support Polymer and Removal of theSide-Chain Protecting Groups

When the synthesis is complete, the peptide is cleaved from the supportphase and its side-chain protecting groups are removed.

In cases where peptides with an amidated C-terminus (—CONH₂) or with aC-terminal carboxyl group (—COOH) are prepared by Boc strategy on anMBHA, Merrifield, or PAM resin, the removal of the peptide from theresin is performed by treatment with a reagent such as liquid hydrogenfluoride (HF). This is also the case for peptides synthesized on theBoc-Agm-SPA-MBHA resin. In some instances, the liquid HF also cleavesall the remaining side chain protecting groups. However, if side chainprotecting groups resistant to HF treatment are present on the peptide,additional cleavage steps should be performed in order to remove theseprotecting groups. Thus, Fm and Fmoc protecting groups are removed bytreatment with 20% piperidine in DMF, while All and Alloc groups areremoved by treatment with Pd(PPh₃)₄catalyst and nucleophilic scavengers,prior to or after the HF treatment.

Suitably, the dried and protected peptide-resin is treated with amixture consisting of 1.0 ml m-cresol and 10 ml anhydrous hydrogenfluoride per gram of peptide-resin for 60-120 min at 0° C. to cleave thepeptide from the resin as well as to remove the HF-labile side chainprotecting groups. After the removal of the hydrogen fluoride under astream of nitrogen and vacuum, the free peptides are precipitated withether, filtered, washed with ether and ethyl acetate, extracted with 50%acetic acid, and lyophilized.

In cases where peptides with an ethylamide (—NHEt) C-terminus areprepared by Boc strategy on the Merrifield or HMBA-MBHA resin, theprotected peptides are first cleaved from the resin by ethylamine(EtNH₂) mediated aminolysis. Suitably, liquid EtNH₂ is transferred intoa cooled, heavy-walled glass flask that contains the dried and protectedpeptide-resin. The quantity of liquid EtNH₂ should be sufficient tocover the peptide-resin. The flask is stoppered, and shaken with theliquid EtNH₂ for 3.5 hours at room temperature in order to allow for thereaction to take place. After this, the flask is cooled in a dry icebath, opened, and the liquid EtNH₂ is filtered off the solid residuethat contains a mixture of resin and cleaved peptide, the peptide stillhaving the protecting groups attached. The solid residue is dried andsubjected to HF treatment as described above, in order to remove theside chain protecting groups of the peptide.

6. Purification.

The purification of the crude peptides can be effected using procedureswell known in peptide chemistry. For example, purification may beperformed on a MacRabbit HPLC system (Rainin Instrument Co. Inc.,Woburn, Mass.) with a Knauer UV Photometer and a Kipp and Zonen BD40Recorder using a Vydac 218TP51 0 reversed-phase column (10×250 mm,packed with C18 silica gel, 300 Å pore size, 5 u.m particle size) (TheSeparations Group Inc., Hesperia, Calif.). The column is eluted with asolvent system consisting of (A) 0.1% aqueous TFA and (B) 0.1% TFA in70% aqueous MeCN in a linear gradient mode (e.g., 30-55% B in 120 min).The eluent is monitored at 220 nm, and fractions are examined byanalytical HPLC using a Hewlett-Packard Model HP-1090 liquidchromatograph and pooled to give maximum purity. Analytical HPLC iscarried out on a Vydac 218TP52 reversed-phase column (2×250 mm, C18, 300Å, 5 μm) using isocratic elution with a solvent system consisting of (A)and (B) defined above. The peaks are monitored at 220 and 280 nm. Thepeptides are judged to be substantially (>95%) pure by analytical HPLC.Molecular masses are checked by electrospray mass spectrometry, and theexpected amino acid compositions are confirmed by amino acid analysis.

D. Pharmaceutical Compositions and Mode of Administration

The peptides of the invention may be administered in the form ofpharmaceutically acceptable, nontoxic salts, such as acid additionsalts. Illustrative of such acid addition salts are hydrochloride,hydrobromide, sulphate, phosphate, fumarate, gluconate, tannate,maleate, acetate, trifluoroacetate, citrate, benzoate, succinate,alginate, pamoate, malate, ascorbate, tartarate, and the like.Particularly preferred antagonists are salts of low solubility, e.g.,pamoate salts and the like. These exhibit long duration of activity.

The compounds of the present invention are suitably administered tosubject humans or animals subcutaneously (s.c.), intramuscularly (i.m.),or intravenously (i.v); intranasally or by pulmonary inhalation; bytransdermal delivery; or in a depot form (e.g., microcapsules,microgranules, or cylindrical rod like implants) formulated from abiodegradable suitable polymer (such as D,L-lactide-coglycolide), theformer two depot modes being preferred. Other equivalent modes ofadministration are also within the scope of this invention, i.e.,continuous drip, cutaneous patches, depot injections, infusion pump andtime release modes such as microcapsules and the like. Administration isin any physiologically acceptable injectable carrier, physiologicalsaline being acceptable, though other carriers known to the art may alsobe used.

The peptides are preferably administered parenterally, intramuscularly,subcutaneously or intravenously with a pharmaceutically acceptablecarrier such as isotonic saline. Alternatively, the peptides may beadministered as an intranasal spray with an appropriate carrier or bypulmonary inhalation. One suitable route of administration is a depotform formulated from a biodegradable suitable polymer, e.g.,poly-D,L-lactide-coglycolide as microcapsules, microgranules orcylindrical implants containing dispersed antagonistic compounds.

The amount of peptide needed depends on the type of pharmaceuticalcomposition and on the mode of administration. In cases where humansubjects receive solutions of GH-RH antagonists, administered by i.m. ors.c. injection, or in the form of intranasal spray or pulmonaryinhalation, the typical doses are between 2-20 mg/day/patient, givenonce a day or divided into 2-4 administrations/day. When the GH-RHantagonists are administered intravenously to human patients, typicaldoses are in the range of 8-80 μg/kg of body weight/day, divided into1-4 bolus injections/day or given as a continuous infusion. When depotpreparations of the GH-RH antagonists are used, e.g. by i.m. injectionof pamoate salts or other salts of low solubility, or by i.m. or s.c.administration of microcapsules, microgranules, or implants containingthe antagonistic compounds dispersed in a biodegradable polymer, thetypical doses are between 1-10 mg antagonist/day/patient.

E. Therapeutic Uses of GH-RH Antagonists

The most important therapeutic applications of GH-RH antagonists areexpected to be in the field of oncology and endocrinology. Some of theGH-RH antagonists act predominantly at the pituitary level and havestronger endocrine effects, inhibiting the GH-RH-evoked GH release, andultimately decreasing the serum levels of GH and IGF-1. Other GH-RHantagonists act predominantly at the tumor level, by blocking thetumoral receptors for GH-RH, reducing the production of variousautocrine/paracrine tumor growth factors (such as IGF-1, IGF-11, GH,VEGF, FGF) and/or downregulating their receptors (IGF-1 receptors, GHreceptors, VEGF receptors, FGF receptors, EGF receptors EGFR, humanepidermal growth factor receptors HER2, HER3, and HER4), in addition toinhibiting the intracellular signaling pathways involved in theproliferation and survival of the cancer cells, and thus exert strongerinhibitory effects on tumor growth. These antagonists can also be usedas carrier systems linked to radionuclides for tumor localization ortherapy, or conjugated to chemotherapeutic agents or toxins. Such hybridcompounds can be actively targeted to cancer for diagnostic ortherapeutic purposes. Yet other GH-RH antagonists act by multiplemechanisms of action, that is by endocrine mechanisms and by directeffects on tumors at the same time. Thus, the main therapeuticindications of various GH-RH antagonists differ based on theirpreferential mechanism of action.

Analogs of GH-RH with antagonistic action on the pituitary can be usedin situations where it is beneficial to suppress serum levels of GH andIGF1I. Thus they are indicated for the therapy of endocrine disorderscharacterized by excessive production of GH and IGF-1, as well as forthe treatment of cancers that express receptors for IGF-1, IGF-11, orGH, and the proliferation of which is stimulated by these growthfactors.

Somatostatin analogs and GH antagonists are also available for thetreatment of endocrine conditions caused by GH and IGF-1. However, GH-RHantagonists offer unique therapeutical benefits unobtainable by the useof somatostatin analogs and GH antagonists.

These benefits are due to the multiple mechanisms of action of GH-RHantagonists, namely that they exert GH- and IGF-l-independent directeffects on tumors and other target sites, in addition to inhibiting theendocrine axis for GH and IGF-1. GH-RH antagonists may be given alone ortogether with somatostatin analogs, a combination which more completelysuppresses GH and IGF-1 levels. An undesired side-effect of GHantagonists, which can be avoided by the administration of GH-RHantagonists, is the elevation of serum GH levels through a feed-backmechanism.

One disease caused by excess growth hormone is acromegaly, which ismanifested in an abnormal enlargement of the bones of the face andextremities. GH-RH antagonists could alleviate the clinicalmanifestations of acromegaly, e.g. the enlargement of facial andextremity bones, the enlargement of heart, and other structural andfunctional abnormalities of the cardiovascular system. The GH-RHantagonists may also be used to treat diabetic retinopathy (the maincause of blindness in diabetics) and diabetic nephropathy, in whichdamage to the eye and kidney respectively is thought to be due to GH.Diabetic patients can also benefit from the increased insulinsensitivity produced by GH-RH antagonists, an effect linked to theability of these compounds to reduce the GH and IGF-1 levels. Inaddition, since they inhibit GH release, GH-RH antagonists can be usedto slow down the progression of muscular dystrophy.

Drugs with anti-growth factor properties such as GH-RH antagonists canalso be of benefit in controlling or slowing down the progression ofsome clinicopathologic processes in conditions such as idiopathicpulmonary fibrosis, systemic sclerosis and hypertrophic cardiomyopathy,where the present medical therapies have relatively little to offer. Inaddition, no drug therapy has been shown to be effective in decreasingthe incidence of restenosis after percutaneous transluminal coronaryangioplasty (PTCA) and new approaches must be devised, including the useof GH-RH antagonists. Some gynecologic conditions, such as myoma,endometriosis, and polycystic ovary syndrome, can also be treated withGH-RH antagonists in combination with luteinizing hormone-releasinghormone (LH-RH) agonists or antagonists. GH-RH antagonists are alsoavailable for treatment of benign prostatic hyperplasia (BPH), andhyperplastic and benign proliferative disorders of other normal organsin which the GH-RH receptors are present. In addition, GH-RH antagonistscan be of benefit for the treatment of autoimmune diseases includingmultiple sclerosis.

However, the main applications of GH-RH antagonists are in the field ofcancer. GH-RH antagonists, especially those with strong direct effectsat the tumor level, are indicated for the inhibition of growth ofprimary tumors and for the suppression of their metastatic spread. Sincethe antiproliferative effects of GH-RH antagonists are exerted byseveral mechanisms, these compounds are available for the treatment of alarge variety of cancers, such as those that depend onautocrine/paracrine and endocrine stimulation by GH-RH, IGF-1, IGF-11,GH, VEGF, and FGF, and cancers dependent on growth factor receptors suchas GH-RH receptors, IGF-1 receptors, GH receptors, VEGF receptors, FGFreceptors, and receptors of the EGF receptor/HER family (EGF receptorsor HER1, HER2, HER3, and HER4). GH-RH antagonists also inhibit thephosphorylation of MAP kinases ERK_(1/2), c-jun kinase JNK, and thephosphorylation of AKT, and thus are available for the treatment ofcancers dependent on the MEK-ERK and PI3K-AKT-mTOR signaling pathways.In addition, GH-RH antagonists decrease the levels of cyclo-oxygenase 2(COX2), and mutant Ras proteins. Thus, GH-RH antagonists are alsoavailable for the treatment of cancers dependent on the mentionedproliferative and anti-apoptotic (survival) signaling pathways,signaling molecules, and oncoproteins. For maximum therapeutic benefits,GH-RH antagonists are available for use as single therapeutic agents, orin combination therapeutic regimens with chemotherapeutic and cytotoxicagents, targeted therapeutic agents, and radiotherapy.

GH-RH antagonists are available for the treatment of tumors that expressGH-RH receptors and use GH-RH as an autocrine/paracrine growth factor.Such malignancies include, but are not limited to, cancers of the lung,prostate, breast, ovary, endometrium, esophagus, stomach, intestine,pancreas, kidney, urinary bladder, bone, liver, as well asglioblastomas, pheochromocytomas, melanomas, and lymphomas. By blockingthe tumoral receptors for GH-RH, these antagonists prevent thestimulatory action of GH-RH, resulting in inhibition of tumor growth.

One advantage of GH-RH antagonists over somatostatin analogs is based onthe fact that GH-RH antagonists may be utilized for suppression oftumors which do not have somatostatin receptors but express the tumoralreceptors for GH-RH, for example human osteogenic sarcomas.

Malignancies that express the IGF-1 receptors, and depend on IGF-1and/or IGF-11 as growth factors, are available for therapy with GH-RHantagonists. These malignancies include, among others, lung cancers,prostatic, breast, ovarian, endometrial, gastric, colorectal,pancreatic, renal, and hepatic cancers, sarcomas, and brain tumors. Theability of GH-RH antagonists to decrease serum IGF-I levels, inhibit theautocrine/paracrine production of IGF-1 and/or IGF-11 in the tumortissue, and downregulate the expression level of IGF-1 receptor, isbeneficial for cancer therapy.

Breast cancers and other types of cancer that depend on GH as a growthfactor, can be treated with GH-RH antagonists. The ability of GH-RHantagonists to reduce serum GH levels, inhibit the autocrine productionof GH, and downregulate GH receptor expression, beneficiate thetreatment of certain breast cancers and other types of tumors as well.

GH-RH antagonists are available as inhibitors of angiogenesis, in viewof their inhibitory activity on the synthesis of VEGF, bFGF, and theirreceptors (receptors for VEGF and bFGF) by tumor tissues and normalendothelial cells, and considering their antiproliferative effect onendothelial cells. Thus GH-RH antagonists could be beneficial for thetreatment of those tumors that strongly depend on VEGF, bFGF, andneoangiogenesis.

EXAMPLES

The present invention is described in connection with the followingexamples which are set forth for the purposes of illustration only. Inthe examples, optically active protected amino acids in theL-configuration are used except where specifically noted.

The following Examples set forth suitable methods of synthesizing thenovel GH-RH antagonists by the solid-phase technique.

Example I

(CH₃(CH₂)₁₀CO-Ada)⁰-Tyri-D-Arg2-Asp³-Ala-lle⁵-Cpa⁶-Thr⁷-Ala⁸-Har⁹-Tyr(Me)¹⁰-His¹¹-Lys¹²-Var³-Leu¹⁴-Abu¹⁵-Gln¹⁶-Leu¹⁷-Ser¹⁸-Ala¹⁹-His²⁰-Lys²¹-Leu²²-Leu²³-Gln²⁴-Asp²⁵-lle²⁶-Nle²⁷-D-Arg²⁸-Har²⁹-NH₂(Peptide 11125)

[(CH₃(CH₂)₁₀CO-Ada)^(o)-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His^(n), Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂

The synthesis is conducted in a stepwise manner using manual solid phasepeptide synthesis equipment. Briefly, para-methylbenzhydrylamine (MBHA)resin (Bachem, King of Prussia, Pa.) (720 mg, 0.50 mmol) is neutralizedwith 5% DlEA in DCM and washed according to the protocol described inTable I. The solution of Boc-Har(NO₂)—OH (500 mg, 1.5 mmol) in DMF-DCM(1:1) is shaken with the neutralized resin and DIC (235 μl, 1.5 mmol) ina manual solid phase peptide synthesis apparatus for 1 hour. After thecompletion of the coupling reaction is proved by negative ninhydrintest, the deprotection and neutralization protocols described in Table Iare performed in order to remove the Boc protecting group and preparethe peptide-resin for coupling of the next amino acid. The synthesis iscontinued and the peptide chain is built stepwise by coupling thefollowing protected amino acids in the indicated order on the resin toobtain the desired peptide sequence: Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH.

These protected amino acid residues (also commonly available fromBachem, Novabiochem, and Peptides International) are represented aboveaccording to a well accepted convention. The suitable protecting groupfor the side chain functional group of particular amino acids appears inparentheses. The OH groups in the above formulae indicate that thecarboxyl terminus of each residue is free.

The protected amino acids (1.5 mmol each) are coupled with DIC (235 μl,1.5 mmol) with the exceptions of Boc-Asn-OH and Boc-Gln-OH which arecoupled with their preformed HOBt esters. After removal of theN^((omega))-Boc protecting group from Ada^(o), the peptide is acylatedovernight with dodecanoic acid [CH₃(CH₂)₁₀COOH] (601 mg, 3 mmol) usingDIC (235 μl, 1.5 mmol) as a coupling agent.

In order to cleave the peptide from the resin and deprotect it, aportion of 250 mg of the dried peptide resin is stirred with 0.5 mlm-cresol and 5 ml hydrogen fluoride (HF) at 0° C. for 2 hours. Afterevaporation of the HF under a stream of nitrogen and in vacuo, theresidue is washed with dry diethyl ether and ethyl acetate. The cleavedand deprotected peptide is dissolved in 50% acetic acid and separatedfrom the resin by filtration. After dilution with water andlyophilization, 135 mg crude product is obtained.

The crude peptide is checked by analytical HPLC using a Hewlett-PackardModel HP-1090 liquid chromatograph with a Supelco Discovery HS C18reversed-phase column (2.1 mm×5 cm, packed with C18 silica gel, 120 Åpore size, 3 μm particle size) (Supelco, Bellefonte, Pa.) and lineargradient elution (e.g., 40-70% B), with a solvent system consisting of(A) 0.1% aqueous TFA and (B) 0.1% TFA in 70% aqueous MeCN. Forpurification by semipreparative HPLC, 135 mg of crude peptide isdissolved in AcOH/H₂O, stirred, filtered and applied on a BeckmanUltraprep ODS column (21.2 mm×15 cm, packed with C18 silica gel, 300 Åpore size, 10 μm particle size). The column is eluted with a solventsystem described above in a linear gradient mode (e.g., 40-60% B in 120min); flow rate 12 mL/min. The eluent is monitored at 220 nm, andfractions are examined by analytical HPLC. Fractions with purity higherthan 95% are pooled and lyophilized to give 15.5 mg pure product. Theanalytical HPLC is carried out on a Supelco C18 reversed-phase columndescribed above using isocratic elution with a solvent system describedabove with a flow rate of 0.2 mL/min. The peaks are monitored at 220 and280 nm. The product is judged to be substantially (>95%) pure byanalytical HPLC. Molecular mass is checked by electrospray massspectrometry, and the expected amino acid composition is confirmed byamino acid analysis.

In accordance with the above procedure Peptide 1109, Peptide 1111,Peptide 11113, Peptide 11115, Peptide 11117, Peptide 11107, Peptide11109, Peptide 11111, Peptide 11113, Peptide 11115, Peptide 11117,Peptide 11119, Peptide 11121, Peptide 11123, Peptide 11207, Peptide11209, Peptide 11211, Peptide 11213, Peptide 11215, Peptide 11307,Peptide 11309, Peptide 11315, Peptide 11317, Peptide 11319, Peptide11321, Peptide 11407, Peptide 11408, Peptide 11409, Peptide 11411,Peptide 11413, Peptide 11417, Peptide 11419, Peptide 11421, Peptide11423, Peptide 11425, Peptide 11427, Peptide 11429, Peptide 11431,Peptide 11433, Peptide 11435, Peptide 11437, Peptide 11439, Peptide11441, Peptide 11443, Peptide 11445, Peptide 11447, Peptide 11449,Peptide 11451, Peptide 11453, Peptide 11455, Peptide 11457, Peptide11459, Peptide 11461, Peptide 11463, Peptide 11465, Peptide 11467,Peptide 11469, Peptide 11471, Peptide 11473, Peptide 11475, Peptide11477, Peptide 11479, Peptide 11481, Peptide 11483, Peptide 11485,Peptide 11487, Peptide 11491, Peptide 11497, Peptide 11499, Peptide11501, Peptide 11503, Peptide 11513, Peptide 11515, Peptide 11521,Peptide 11523, Peptide 11525, Peptide 11601, Peptide 11602, Peptide11603, Peptide 11610, Peptide 11611, Peptide 11612, Peptide 11620,Peptide 11621, Peptide 11630, Peptide 11701, Peptide 11702, Peptide11703, and Peptide 11704 are synthesized in the same manner as Peptide11125, except that these peptides also contain other amino acidsubstitutions in the peptide sequence, different C-termini, and otheracyl moieties at their N-termini. The details for these syntheses areset forth below.

For the synthesis of Peptide 1109, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, Glu¹⁷,His²⁰, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protected aminoacids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Glu(OcHx)-OH,Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH,Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 1111, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His²⁰,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har29]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-(Me-Ala)-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 1113, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 1115, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,(Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hgH-RH (1-29) NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(Me)₂-OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)-OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH. For the synthesisof Peptide 1117, the chemical structure of which is [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hgH-RH (1-29)NH₂, the following protected amino acids arecoupled in the indicated order on the MBHA resin: Boc-Har(NO₂)—OH,Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed by acylation with PhAc-OH.

For the synthesis of Peptide 11107, the chemical structure of which is[(N-Me-Aib)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, and Boc-(N-Me-Aib)-OH. For the synthesis of Peptide11109, the chemical structure of which is [Dca⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, the following protected amino acids are coupledin the indicated order on the MBHA resin: Boc-Har(NO₂)—OH,Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed by acylation with Dca-OH.

For the synthesis of Peptide 11111, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylation with Ac—OH. For thesynthesis of Peptide 11113, the chemical structure of which is[Fer⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protected amino acids arecoupled in the indicated order on the MBHA resin: Boc-Har(NO₂)—OH,Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed by acylation with Fer-OH.

For the synthesis of Peptide 11115, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11117, the chemical structure of which is[(PhAc-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11119, the chemical structure of which is[(Ac-Ada-D-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-D-Phe-OH, Boc-Ada-OH, followed by acylation withAc—OH. For the synthesis of Peptide 11121, the chemical structure ofwhich is [(Ac-Ada-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Phe-OH,Boc-Ada-OH, followed by acylation with Ac—OH. For the synthesis ofPeptide 11123, the chemical structure of which is [(Dca-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protected amino acids arecoupled in the indicated order on the MBHA resin: Boc-Har(NO₂)—OH,Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed byacylation with Dca-OH.

For the synthesis of Peptide 11207, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11209, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹-Apa³⁰]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Apa-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11211, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11213, the chemical structure of which is[Oct⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(et)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Et)-OH, Boc-His(Bom)-OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with Oct-OH.

For the synthesis of Peptide 11215, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Ada-OH, Boc-Arg(Tos)-OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11307, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Amc-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11309, the chemical structure of which is[(Me-NH-Sub)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with Me-NH-Sub-OH.

For the synthesis of Peptide 11315, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂ the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Amc-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11317, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11319, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(et)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Et)-OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed byacylation with Ac—OH.

For the synthesis of Peptide 11321, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Arg(Tos)-OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11407, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala⁴)Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-(Me-Ala)-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylationwith Ac—OH.

For the synthesis of Peptide 11408, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har29]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11409, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-(Me-Ala)-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11411, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with PhAc-OH.

For the synthesis of Peptide 11413, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, 3-Pal⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-3-Pal-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11417, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH,Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11419, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed byacylation with PhAc-OH.

For the synthesis of Peptide 11421, the chemical structure of which is[(N-Me-Aib)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, andBoc-(N-Me-Aib)-OH.

For the synthesis of Peptide 11423, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Dip⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Dip-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed byacylation with PhAc-OH.

For the synthesis of Peptide 11321, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Arg(Tos)-OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11407, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-(Me-Ala)-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylationwith Ac—OH.

For the synthesis of Peptide 11408, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11409, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-(Me-Ala)-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11411, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followedbyacylation with PhAc-OH.

For the synthesis of Peptide 11413, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, 3-Pal⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-3-Pal-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11417, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Amc-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11419, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed byacylation with PhAc-OH.

For the synthesis of Peptide 11421, the chemical structure of which is[(N-Me-Aib)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, andBoc-(N-Me-Aib)-OH.

For the synthesis of Peptide 11423, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Dip⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Dip-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed byacylation with PhAc-OH.

For the synthesis of Peptide 11425, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Lys(PhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His)¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(Boc)-OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.F or the synthesisof Peptide 11427, the chemical structure of which is [(N-Me-Aib)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Lys((N-Me-Aib)-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His)¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(Boc)-OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, andBoc-(N-Me-Aib)-OH.

For the synthesis of Peptide 11429, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂,the MBHA resin is first loaded with Boc-Lys(Fmoc)-OH, followed byremoval of the Fmoc protecting group as described in Table II(section 1. Deprotection), and acylation of the ε-amino group of Lyswith octanoic acid (Oct-OH). Subsequently, the rest of the peptide chainis constructed in the usual way, using Boc strategy, by coupling thefollowing protected amino acids in the indicated order: Boc-β-Ala-OH,Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11431, the chemical structure of which is[(N-Me-Aib)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂, the MBHA resin is first loadedwith Boc-Lys(Fmoc)-OH, followed by removal of the Fmoc protecting groupas described in Table II (section 1. Deprotection), and acylation of theε-amino group of Lys with octanoic acid (Oct-OH). Subsequently, the restof the peptide chain is constructed in the usual way, using Bocstrategy, by coupling the following protected amino acids in theindicated order: Boc-β-Ala-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, andBoc-(N-Me-Aib)-OH.

For the synthesis of Peptide 11433, the chemical structure of which is[Nac⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,followed byacylation with Nac-OH.

For the synthesis of Peptide 11435, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed byacylation with Ac—OH.

For the synthesis of Peptide 11437, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed byacylation with Dca-OH.

For the synthesis of Peptide 11439, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed byacylation with Ac—OH.

For the synthesis of Peptide 11441, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,(Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, the following protected amino acids are coupledin the indicated order on the MBHA resin: Boc-Har(NO₂)—OH,Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11443, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed byacylation with Dca-OH.

For the synthesis of Peptide 11445, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,(Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, the following protected amino acids are coupledin the indicated order on the MBHA resin: Boc-Har(NO₂)—OH,Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Lys(Me)₂-OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Dca-OH.

For the synthesis of Peptide 11447, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,Har²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11449, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, Har²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed byacylation with Ac—OH.

For the synthesis of Peptide 11451, the chemical structure of which is[(Nac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Nac-OH.

For the synthesis of Peptide 11453, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Dca-OH.

For the synthesis of Peptide 11455, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₂A-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2ClZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11457, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with PhAc-OH.

For the synthesis of Peptide 11459, the chemical structure of which is[(PhAc-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹ Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with PhAc-OH.

For the synthesis of Peptide 11461, the chemical structure of which is[(Ac-Ada-Phe)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹ Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Phe-OH,Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11463, the chemical structure of which is[PhAc⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹ Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AMC³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with PhAc-OH.

For the synthesis of Peptide 11465, the chemical structure of which isis [PhAc⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with PhAc-OH.

For the synthesis of Peptide 11467, the chemical structure of which is[Ada-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, and Boc-Ada-OH.

For the synthesis of Peptide 11469, the chemical structure of which is[Ac-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11471, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Lys(Ac-Ada-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His-)¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(Boc)-OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11473, the chemical structure of which is[(PHAc-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11475, the chemical structure of which is[(Ac-Ada-D-Phe)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-D-Phe-OH, Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11477, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, Glu¹⁷, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Glu(OcHx)-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11479, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹ D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11481, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-ε-Lys(α-NH₂)³⁰-Ahx³¹]hGH-RH(1-29)NH₂, the following protectedamino acids are coupled in the indicated order on the MBHA resin:Boc-Ahx-OH, Z-Lys(Boc)-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11483, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₄P—OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11485, the chemical structure of which is[(CH₃(CH₂)₁₀CO-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂,the following protected amino acids are coupled in the indicated orderon the MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with CH₃(CH₂)₁₀COOH.

For the synthesis of Peptide 11487, the chemical structure of which is[(CH₃(CH₂)₁₀CO-Ada)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂,the following protected amino acids are coupled in the indicated orderon the MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with CH₃(CH₂)₁₀COOH.

For the synthesis of Peptide 11491, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹ D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Dca-OH.

For the synthesis of Peptide 11497, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹ D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹ Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)O, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11499, the chemical structure of which is[PhAc⁰-Tyr¹ D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹ Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH,Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11501, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂, the MBHA resin is first loadedwith Boc-Lys(Fmoc)-OH, followed by removal of the Fmoc protecting groupas described in Table II (section 1. Deprotection), and acylation of theε-amino group of Lys with octanoic acid (Oct-OH). Subsequently, the restof the peptide chain is constructed in the usual way, using Bocstrategy, by coupling the following protected amino acids in theindicated order: Boc-β-Ala-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11503, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂, the MBHA resin is first loadedwith Boc-Lys(Fmoc)-OH, followed by removal of the Fmoc protecting groupas described in Table II (section 1. Deprotection), and acylation of theε-amino group of Lys with octanoic acid (Oct-OH). Subsequently, the restof the peptide chain is constructed in the usual way, using Bocstrategy, by coupling the following protected amino acids in theindicated order: Boc-β-Ala-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Dca-OH.

For the synthesis of Peptide 11513, the chemical structure of which[(Dca⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with Dca-OH.

For the synthesis of Peptide 11515, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Lys(Dca-Ada-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me-His′)¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(Boc)-OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylation with Dca-OH.

For the synthesis of Peptide 11521, the chemical structure of which is[(Dca-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His, Orn¹²,Orn¹⁵, Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂,the following protected amino acids are coupled in the indicated orderon the MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Orn(2CIZ)—OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Amc-OH, followed by acylation with Dca-OH.

For the synthesis of Peptide 11523, the chemical structure of which is[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Orn¹⁵,Glu¹⁷, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Glu(OcHx)-OH, Boc-Gln-OH, Boc-Orn(2CIZ)—OH,Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, followed by acylation with PhAc-OH.

For the synthesis of Peptide 11525, the chemical structure of which isis [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His, Orn¹², Orn¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Orn(2CIZ)—OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with PhAc-OH.

For the synthesis of Peptide 11601, the chemical structure of which is[(CH₃(CH₂)₁₀CO-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, the following protected amino acids are coupledin the indicated order on the MBHA resin: Boc-Har(NO₂)—OH,Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH,Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylation with CH₃(CH₂)₁₀COOH.

For the synthesis of Peptide 11602, the chemical structure of which is[(CPhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with PhAc-OH.

For the synthesis of Peptide 11603, the chemical structure of which is[(DCA-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Dca-OH.

For the synthesis of Peptide 11610, the chemical structure of which[PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, (Phe(F)₅)⁶, His¹¹, Orn¹², Abu¹⁵,His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Phe(F)₅—OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followedbyacylation with PhAc-OH.

For the synthesis of Peptide 11611, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂,the following protected amino acids are coupled in the indicated orderon the MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH,Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11612, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂,the following protected amino acids are coupled in the indicated orderon the MBHA resin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Phe(F)₅—OH,Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylation with Ac—OH.

For the synthesis of Peptide 11620, the chemical structure of which[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Arg²⁹, Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Arg(Tos)-OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Amc-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11621, the chemical structure of which is[(Me-NH-Sub⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹, Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Ada-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, followed byacylation with Me-NH-Sub-OH.

For the synthesis of Peptide 11630, the chemical structure of which is[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, the followingprotected amino acids are coupled in the indicated order on the MBHAresin: Boc-Amc-OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH,Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH,Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH,Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH,Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH,Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH,followed by acylation with Ac—OH.

For the synthesis of Peptide 11701, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orm¹²,Abu¹⁵, Glu¹⁷, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂, thefollowing protected amino acids are coupled in the indicated order onthe MBHA resin: Boc-AE₄P—OH, Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Orn(2CIZ)—OH, Boc-Arg(Tos)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Glu(OcHx)-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Ada-OH, followed by acylation with Dca-OH.

For the synthesis of Peptide 11702, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, Glu¹⁷, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂, the following protected amino acids arecoupled in the indicated order on the MBHA resin: Boc-AE₄P—OH,Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Glu(OcHx)-OH,Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH,Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylationwith Dca-OH.

For the synthesis of Peptide 11703, the chemical structure of which is[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, Glu¹⁷, Har²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂, the following protected amino acids arecoupled in the indicated order on the MBHA resin: Boc-AE₄P—OH,Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-Har(NO2)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Glu(OcHx)-OH,Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH,Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylationwith Dca-OH.

For the synthesis of Peptide 11704, the chemical structure of which is[(CH₃(CH₂)₁₀CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂, the following protected amino acids arecoupled in the indicated order on the MBHA resin: Boc-AE₄P—OH,Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Ada-OH, followed by acylation with CH₃(CH₂)₁₀COOH.

HF cleavage and deprotection, and subsequent purification bysemipreparative HPLC of Peptide 1109, Peptide 1111, Peptide 1113,Peptide 1115, Peptide 1117, Peptide 11107, Peptide 11109, Peptide 11111,Peptide 11113, Peptide 11115, Peptide, Peptide 11119, Peptide 11121,Peptide 11123, Peptide 11207, Peptide 11209, Peptide, Peptide 11213,Peptide 11215, Peptide 11307, Peptide 11309, Peptide 11315, Peptide11317, Peptide 11319, Peptide 11321, Peptide 11407, Peptide 11408,Peptide 11409, Peptide 11411, Peptide 11413, Peptide 11417, Peptide11419, Peptide 11421, Peptide 11423, Peptide 11425, Peptide 11427,Peptide 11429, Peptide 11431, Peptide 11433, Peptide 11435, Peptide11437, Peptide 11439, Peptide 11441, Peptide 11443, Peptide 11445,Peptide 11447, Peptide 11449, Peptide 11451, Peptide 11453, Peptide11455, Peptide 11457, Peptide 11459, Peptide 11461, Peptide 11463,Peptide 11465, Peptide 11467, Peptide 11469, Peptide 11471, Peptide11473, Peptide 11475, Peptide 11477, Peptide 11479, Peptide 11481,Peptide 11483, Peptide 11485, Peptide 11487, Peptide 11491, Peptide11497, Peptide 11499, Peptide 11501, Peptide 11503, Peptide 11513,Peptide 11515, Peptide 11521, Peptide 11523, Peptide 11525, Peptide11601, Peptide 11602, Peptide 11603, Peptide 11610, Peptide 11611,Peptide 11612, Peptide 11620, Peptide 11621, Peptide 11630, Peptide11701, Peptide 11702, Peptide 11703, and Peptide 11704 are done asdescribed in the case of Peptide 11125. The purified compounds arejudged to be substantially (>95%) pure by analytical HPLC. Theirmolecular masses are checked by electrospray mass spectrometry, and theexpected amino acid compositions are confirmed by amino acid analysis.

Example II

(Ac-Amc)⁰-Tyr, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Agm³⁰]hGH-RH(1-29) (Peptide 11313). Thesynthesis is conducted in a stepwise manner using manual solid phasepeptide synthesis equipment. The starting material of the synthesis isBoc-agmatine-N^(G)-sulfonyl-phenoxyacetyl-MBHA (Boc-Agm-SPA-MBHA) resinwith a substitution of 0.3 mmol/g, which was obtained commercially fromCalifornia Peptide Research, Inc. (Napa, Calif.). The synthesis of thisresin has been described in U.S. Pat. No. 4,914,189 and in thescientific literature (Zarandi M, Serfozo P, Zsigo J, Bokser L, JanakyT, Olsen D B, Bajusz S, Schally A V, Int. J. Peptide Protein Res. 39:211-217, 1992), hereby incorporated by reference. Briefly,Boc-Agm-SPA-MBHA resin (1.67 g, 0.50 mmol) is pre-swollen in DCM andthen the deprotection and neutralization protocols described in Table Iare performed in order to remove the Boc protecting group and preparethe peptide-resin for coupling of the next amino acid. The synthesis iscontinued and the peptide chain is built stepwise by coupling thefollowing protected amino acids in the indicated order on the resin toobtain the desired peptide sequence: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH,Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH,Boc-Leu-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Amc-OH. The protected amino acids (1.5 mmol each) are coupled withDIC (235 μl, 1.5 mmol) with the exceptions of Boc-Asn-OH and Boc-Gln-OHwhich are coupled with their preformed HOBt esters. After removal of theNO-Boc protecting group from Amco, the peptide is acylated with1-acetylimidazole (220 mg, 2 mmol).

In order to cleave the peptide from the resin and deprotect it, aportion of 500 mg of the dried peptide resin is stirred with 0.5 mLm-cresol and 5 mL hydrogen fluoride (HF) at 0° C. for 2 hours. Afterevaporation of the HF under a stream of nitrogen and in vacuo, theresidue is washed with dry diethyl ether and ethyl acetate. The cleavedand deprotected peptide is dissolved in 50% acetic acid and separatedfrom the resin by filtration. After dilution with water andlyophilization, 210 mg of crude product is obtained.

The peptide is purified by semipreparative H PLC and the elutingfractions are examined by analytical HPLC as described in Example I.Fractions with purity higher than 95% are pooled and lyophilized to give33.0 mg of pure Peptide 11313. Molecular mass is checked by electrospraymass spectrometry, and the expected amino acid composition is confirmedby amino acid analysis.

Peptide 11311, and Peptide 11415 are synthesized in the same manner asPeptide 11313, except that these peptides also contain othersubstitutions.

For the synthesis of Peptide 11311, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, D-Arg²⁸, Agm²⁹]hGH-RH(1-29), the following protected aminoacids are coupled in the indicated order on the Boc-Agm-SPA-MBHA resin:Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH, Boc-Asp(OcHx)-OH, Boc-Gln-OH,Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Ala-OH,Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH, Boc-Abu-OH, Boc-Leu-OH,Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH, Boc-Tyr(Me)-OH,Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH, Boc-Cpa-OH, Boc-Ile-OH,Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH,Boc-Amc-OH, followed by acylation with 1-acetylimidazole.

For the synthesis of Peptide 11415, the chemical structure of which is[(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹-Agm³⁰]hGH-RH(1-29), the following protectedamino acids are coupled in the indicated order on the Boc-Agm-SPA-MBHAresin: Boc-Har(NO₂)—OH, Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Lys(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Lys(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH,Boc-Cpa-OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH, Boc-D-Arg(Tos)-OH,Boc-Tyr(2BrZ)—OH, Boc-Amc-OH, followed by acylation with1-acetylimidazole.

HF cleavage and deprotection, and subsequent purification bysemipreparative HPLC of Peptide 11311 and Peptide 11415 are done asdescribed in the case of Peptide 11313. The purified compounds arejudged to be substantially (>95%) pure by analytical HPLC. Theirmolecular masses are checked by electrospray mass spectrometry, and theexpected amino acid compositions are confirmed by amino acid analysis.

Example III

(PhAc-Ada)⁰-Tyr-D-Arg²-Asp³-Ala⁴-Ile⁵-(Phe(F)₅)⁶-Thr⁷-Ala⁸-Har⁹-Tyr(Me)¹⁰-His¹¹-Orn¹²-Val¹³-Leu¹⁴-Abu¹⁵-Gln¹⁶-Leu¹⁷-Ser¹⁸-Ala¹⁹-His²⁰-Orn²¹-Leu²²-Leu²³-Gln²⁴-Asp²⁵-Ile²⁶-Nle²⁷-D-Arg²⁸-Har²⁹-Agm³⁰.(Peptide 11604) [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹,Agm³⁰]hGH-RH(1-30)

The synthesis is conducted in a stepwise manner using manual solid phasepeptide synthesis equipment. The starting material of the synthesis isBoc-agmatine-N^(G)-sulfonyl-phenoxyacetyl-MBHA (Boc-Agm-SPA-MBHA) resinwith a substitution of 0.3 mmol/g, which was obtained commercially fromCalifornia Peptide Research, Inc. (Napa, Calif.). The synthesis of thisresin has been described in U.S. Pat. No. 4,914,189 and in thescientific literature (Zarandi M, Serfozo P, Zsigo J, Bokser L, JanakyT, Olsen D B, Bajusz S, Schally A V, Int. J. Peptide Protein Res. 39:211-217, 1992), hereby incorporated by reference. Briefly,Boc-Agm-SPA-MBHA resin (1.67 g, 0.50 mmol) is pre-swollen in DCM andthen the deprotection and neutralization protocols described in Table Iare performed in order to remove the Boc protecting group and preparethe peptide-resin for coupling of the next amino acid. The solution ofBoc-Har(NO₂)—OH (500 mg, 1.5 mmol) in DMF-DCM (1:1) is shaken with theneutralized resin and DIC (235 μL, 1.5 mmol) in a manual solid phasepeptide synthesis apparatus for 1 hour. After the completion of thecoupling reaction is proved by negative ninhydrin test, the deprotectionand neutralization protocols described in Table I are performed in orderto remove the Boc protecting group and prepare the peptide-resin forcoupling of the next amino acid. The synthesis is continued and thepeptide chain is built stepwise by coupling the following protectedamino acids in the indicated order on the resin to obtain the desiredpeptide sequence: Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-Ala-OH, Boc-Thr(Bzl)-OH,Boc-Phe(F)₅—OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH.

These protected amino acid residues (also commonly available fromBachem) are represented above according to a well accepted convention.The suitable protecting group for the side chain functional group ofparticular amino acids appears in parentheses. The OH groups in theabove formulae indicate that the carboxyl terminus of each residue isfree.

The protected amino acids (1.5 mmol each) are coupled with DIC (235 μL,1.5 mmol) with the exceptions of Boc-Asn-OH and Boc-Gln-OH which arecoupled with their preformed HOBt esters. After removal of theN^(omega)-Boc protecting group from Ada⁰, the peptide is acylated withphenylacetic acid (PhAc-OH) (272 mg, 2 mmol) using DIC (313 μL, 2 mmol)as a coupling agent.

In order to cleave the peptide from the resin and deprotect it, aportion of 500 mg of the dried peptide resin is stirred with 0.5 mlm-cresol and 5 ml hydrogen fluoride (HF) at 0° C. for 2 hours. Afterevaporation of the HF under a stream of nitrogen and in vacuo, theresidue is washed with dry diethyl ether and ethyl acetate. The cleavedand deprotected peptide is dissolved in 50% acetic acid and separatedfrom the resin by filtration. After dilution with water andlyophilization, 220 mg of crude product is obtained.

The crude peptide is checked by analytical HPLC using a Hewlett-PackardModel HP-1090 liquid chromatograph with a Supelco Discovery HS C18reversed-phase column (2.1 mm×5 cm, packed with C18 silica gel, 120 Åpore size, 3 μm particle size) (Supelco, Bellefonte, Pa.) and lineargradient elution (e.g., 40-70% B), with a solvent system consisting of(A) 0.1% aqueous TFA and (B) 0.1% TFA in 70% aqueous MeCN. Forpurification by semipreparative HPLC, 220 mg of crude peptide isdissolved in AcOH/H₂O, stirred, filtered and applied on a BeckmanUltraprep ODS column (21.2 mm×15 cm, packed with C18 silica gel, 300 Åpore size, 10 μm particle size). The column is eluted with a solventsystem described above in a linear gradient mode (e.g., 40-60% B in 120min); flow rate 10 mL/min. The eluent is monitored at 220 nm, andfractions are examined by analytical HPLC. Fractions with purity higherthan 95% are pooled and lyophilized to give 35.0 mg pure product. Theanalytical HPLC is carried out on a Supelco C18 reversed-phase columndescribed above using isocratic elution with a solvent system describedabove with a flow rate of 0.2 mL/min. The peaks are monitored at 220 and280 nm. The product is judged to be substantially (>95%) pure byanalytical HPLC. Molecular mass is checked by electrospray massspectrometry, and the expected amino acid composition is confirmed byamino acid analysis.

Example IV

(PhAc-Ada)⁰-Tyr¹-D-Arg²-Asp³-Ala⁴-Ile⁵-(Phe(F)₅)⁶-Thr⁷-(Me-Ala)⁸-Har⁹-Tyr(Me)¹⁰-His¹¹-Orn¹²-Val¹³-Leu¹⁴-Abu¹⁵-Gln¹⁶-Leu¹⁷-Ser¹⁸-Ala¹⁹-His²⁰-Orn²¹-Leu²²-Leu²³-Gln²⁴-Asp²⁵-Ile²⁶-Nle²⁷-D-Arg²⁸-Har²⁹-Agm³⁰.(Peptide 11606) [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, (Me-Ala)⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹,Agm³⁰]hGH-RH(1-30)

The synthesis is conducted in a stepwise manner using manual solid phasepeptide synthesis equipment. The starting material of the synthesis isBoc-agmatine-N^(G)-sulfonyl-phenoxyacetyl-MBHA (Boc-Agm-SPA-MBHA) resinwith a substitution of 0.3 mmol/g, which was obtained commercially fromCalifornia Peptide Research, Inc. (Napa, Calif.). The synthesis of thisresin has been described in U.S. Pat. No. 4,914,189 and in thescientific literature (Zarandi M, Serfozo P, Zsigo J, Bokser L, JanakyT, Olsen D B, Bajusz S, Schally A V, Int. J. Peptide Protein Res. 39:211-217, 1992), hereby incorporated by reference. Briefly,Boc-Agm-SPA-MBHA resin (1.67 g, 0.50 mmol) is pre-swollen in DCM andthen the deprotection and neutralization protocols described in Table Iare performed in order to remove the Boc protecting group and preparethe peptide-resin for coupling of the next amino acid. The solution ofBoc-Har(NO₂)—OH (500 mg, 1.5 mmol) in DMF-DCM (1:1) is shaken with theneutralized resin and DIC (235 μL, 1.5 mmol) in a manual solid phasepeptide synthesis apparatus for 1 hour. After the completion of thecoupling reaction is proved by negative ninhydrin test, the deprotectionand neutralization protocols described in Table I are performed in orderto remove the Boc protecting group and prepare the peptide-resin forcoupling of the next amino acid. The synthesis is continued and thepeptide chain is built stepwise by coupling the following protectedamino acids in the indicated order on the resin to obtain the desiredpeptide sequence: Boc-D-Arg(Tos)-OH, Boc-Nle-OH, Boc-Ile-OH,Boc-Asp(OcHx)-OH, Boc-Gln-OH, Boc-Leu-OH, Boc-Leu-OH, Boc-Orn(2CIZ)—OH,Boc-His(Bom)-OH, Boc-Ala-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc-Gln-OH,Boc-Abu-OH, Boc-Leu-OH, Boc-Val-OH, Boc-Orn(2CIZ)—OH, Boc-His(Bom)-OH,Boc-Tyr(Me)-OH, Boc-Har(NO₂)—OH, Boc-(Me-Ala)-OH, Boc-Thr(Bzl)-OH,Boc-Phe(F)₅—OH, Boc-Ile-OH, Boc-Ala-OH, Boc-Asp(OcHx)-OH,Boc-D-Arg(Tos)-OH, Boc-Tyr(2BrZ)—OH, Boc-Ada-OH.

These protected amino acid residues (also commonly available fromBachem) are represented above according to a well accepted convention.The suitable protecting group for the side chain functional group ofparticular amino acids appears in parentheses. The OH groups in theabove formulae indicate that the carboxyl terminus of each residue isfree.

The protected amino acids (1.5 mmol each) are coupled with DIC (235 μL,1.5 mmol) with the exceptions of Boc-Asn-OH and Boc-Gln-OH which arecoupled with their preformed HOBt esters. After removal of theNomes^(a)-Boc protecting group from Ada⁰, the peptide is acylated withphenylacetic acid (PhAc-OH) (272 mg, 2 mmol) using DIC (313 μL, 2 mmol)as a coupling agent.

In order to cleave the peptide from the resin and deprotect it, aportion of 500 mg of the dried peptide resin is stirred with 0.5 mlm-cresol and 5 ml hydrogen fluoride (HF) at 0° C. for 2 hours. Afterevaporation of the HF under a stream of nitrogen and in vacuo, theresidue is washed with dry diethyl ether and ethyl acetate. The cleavedand deprotected peptide is dissolved in 50% acetic acid and separatedfrom the resin by filtration. After dilution with water andlyophilization, 216 mg of crude product is obtained.

The crude peptide is checked by analytical HPLC using a Hewlett-PackardModel HP-1090 liquid chromatograph with a Supelco Discovery HS C18reversed-phase column (2.1 mm×5 cm, packed with C18 silica gel, 120 Åpore size, 3 μm particle size) (Supelco, Bellefonte, Pa.) and lineargradient elution (e.g., 40-70% B), with a solvent system consisting of(A) 0.1% aqueous TFA and (B) 0.1% TFA in 70% aqueous MeCN. Forpurification by semipreparative HPLC, 216 mg of crude peptide isdissolved in AcOH/H₂O, stirred, filtered and applied on a BeckmanUltraprep ODS column (21.2 mm×15 cm, packed with C18 silica gel, 300 Åpore size, 10 μm particle size). The column is eluted with a solventsystem described above in a linear gradient mode (e.g., 40-60% B in 120min); flow rate 10 mL/min. The eluent is monitored at 220 nm, andfractions are examined by analytical HPLC. Fractions with purity higherthan 95% are pooled and lyophilized to give 33.0 mg pure product. Theanalytical HPLC is carried out on a Supelco C18 reversed-phase columndescribed above using isocratic elution with a solvent system describedabove with a flow rate of 0.2 mL/min. The peaks are monitored at 220 and280 nm. The product is judged to be substantially (>95%) pure byanalytical HPLC. Molecular mass is checked by electrospray massspectrometry, and the expected amino acid composition is confirmed byamino acid analysis.

Example V Aqueous Solution for Intramuscular Injection

[(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, 500.0 mg Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂(Peptide 11602) Gelatin, nonantigenic 5.0 mg Water for injection q.s. ad100.0 mLThe gelatin and GH-RH antagonist Peptide 11602 are dissolved in waterfor injection, and then the solution is sterile filtered.

Example VI Long Acting Intramuscular Injectable Formulation (Sesame OilGel)

[(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, 10.0 mg Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹,Agm³⁰]hGH-RH(1-30) (Peptide 11604) Aluminum monostearate, USP 20.0 mgSesame oil q.s. ad 1.0 mLThe aluminum monostearate is combined with the sesame oil and heated to125° C. with stirring until a clear yellow solution forms. This mixtureis then autoclaved for sterility and allowed to cool. The GH-RHantagonist Peptide 11604 is then added aseptically with trituration.Particularly preferred antagonists are salts of low solubility, e.g.,pamoate salts and the like. These exhibit long duration of activity.

Example VII Long Acting Intramuscular (IM) Injectable-BiodegradablePolymer Microcapsules

Microcapsules are made from the following:25/75 glycolide/lactide copolymer (0.5 intrinsic viscosity) 99%[(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰,His¹², Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹,Agm³⁰]hGH-RH(1-30) (Peptide 11606) 1%25 mg of the above microcapsules are suspended in 1.0 mL of thefollowing vehicle:

Dextrose 5.0% CMC, sodium 0.5% Benzyl alcohol 0.9% Tween 80 0.1% Water,purified q.s. ad 100%

Biological Activity in Endocrine and Oncological Assays

The peptides of the present invention were tested in assays in vitro andin vivo for their ability to inhibit the hGH-RH(1-29)NH₂ induced GHrelease. Binding affinities of the compounds to the tumoral GH-RHreceptors were also measured. The antitumor activities of the peptidesand their inhibitory effects on serum IGF-1 and on the tumoral IGF, VEGFand FGF system were evaluated in various cancer models in vivo.Inhibitory effects on phosphorylated PI3K/AKT and MAPK (ERK1/2) werealso measured.

Example VIII Effect of GH-RH Antagonists on PC-3 Human Prostate CancerXenografts in Nude Mice Experiment 1:

Male nude mice were implanted s.c. with 3 mm³ pieces of PC-3 humanhormone-independent prostate cancer tissue on both flanks. When tumorsreached a volume of approx. 50 mm³, the mice were divided into 4experimental groups with 8 to 10 animals in each group and receivedsingle daily injections for 35 days as follows: 1. Control (vehiclesolution); 2. JMR-132 (10 μg/day s.c.); 3. Peptide 1109 (10 μg/days.c.); 4. Peptide 11111 (10 μg/day s.c.); Tumor volumes were measuredonce a week. The experiment was ended on day 35 by sacrificing the miceunder Isoflurane anesthesia. Resulting tumors were cleaned, weighed, andsnap-frozen until further analyses. Statistical analyses of themeasurement results were done by two-tailed t-test, p<0.05 beingconsidered significant. Data are presented as the means±S.E.

Experiment 2:

Experiment 2 was similar to Experiment 1. Experiment 2 was started whenPC-3 tumors had grown to approximately 50 mm³ in volume. At this time,the animals were divided into 5 experimental groups with 8 animals ineach group, and received single daily injections for 14 days asfollows: 1. Control (vehicle solution); 2. JMR-132 (10 μg/day s.c.); 3.Peptide 1109 (5 μg/day s.c.); 4. Peptide 11109 (5 μg/day s.c.); 5.Peptide 11109 (2 μg/day s.c.). Further details of Experiment 2 are thesame as for Experiment 1

Experiment 3:

Male nude mice were implanted s.c. with 3 mm³ pieces of PC-3 humanhormone-independent prostate cancer tissue on both flanks. When tumorsreached a volume of approximately 50 mm³, the mice were divided into 12experimental groups with 8 to 10 animals in each group and receivedsingle daily injections for 28 days as follows: 1. Control (vehiclesolution); 2. JMR-132 (10 μg/day s.c.); 3. Peptide 11113 (2 μg/days.c.); 4. Peptide 11119 (2 μg/day s.c.); 5. Peptide 11209 (2 μg/days.c.); 6. Peptide 11313 (2 μg/day s.c.); 7. Peptide 11408 (2 μg/days.c.); 8. Peptide 11435 (2 μg/day s.c.); 9. Peptide 11457 (2 μg/days.c.); 10. Peptide 11459 (2 μg/day s.c.); 11. Peptide 11469 (2 μg/days.c.); 12. Peptide 11491 (2 μg/day s.c.).

Tumor volumes were measured once a week. The experiment was ended on day28 by sacrificing the mice under Isoflurane anesthesia. Resulting tumorswere cleaned, weighed, and snap-frozen until further analyses.Statistical analyses of the measurement results were done by two-tailedt-test, p<0.05 being considered significant.

Experiment 4:

All experimental details of Experiment 4 are the same as for Experiment3, with the following difference. When tumors reached a volume ofapproximately 50 mm³, the mice were divided into 11 experimental groupswith 8 to 10 animals in each group and received single daily injectionsfor 46 days as follows: 1. Control (vehicle solution); 2. JMR-132 (10μg/day s.c.); 3. Peptide 11123 (2 μg/day s.c.); 4. Peptide 11125 (2μg/day s.c.); 5. Peptide 11213 (2 μg/day s.c.); 6. Peptide 11433 (2μg/day s.c.); 7. Peptide 11473 (2 μg/day s.c.); 8. Peptide 11485 (2μg/day s.c.); 9. Peptide 11497 (2 μg/day s.c.); 10. Peptide 11499 (2μg/day s.c.); 11. Peptide 11521 (2 μg/day s.c.). Tumor volumes weremeasured once a week. The experiment was ended on day 46 by sacrificingthe mice under Isoflurane anesthesia. Resulting tumors were cleaned,weighed, and snap-frozen until further analyses. Statistical analyses ofthe measurement results were done by two-tailed t-test, p<0.05 beingconsidered significant.

Results

Experiment 1:

Among the GH-RH antagonists tested, Peptide 1109 and Peptide 11111exerted a significant inhibitory effect on the growth of PC-3 tumors,while the effect of reference peptide JMR-132 was not significant (TableIII). Abreviated reference JMR-132 means [PhAc⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂.

TABLE III Experiment 1: Effect of Treatment with GH-RH Antagonists onPC-3 Human Prostate Cancer Xenografts in Nude Mice SignificanceSignificance Tumor growth versus versus Group after 5 weeks (%) controlJMR-132 Control  6701 ± 2541 JMR-132 2820 ± 498 0.15 (N.S.) Peptide 11091502 ± 405 0.048 0.0163 Peptide 11111 1215 ± 243 0.043 0.00707 N.S., notsignificant

Experiment 2:

Peptide 1109, used at a dose of 5 u.g/day, as well as Peptide 11109,used at the doses of 5 u.g/day and 2 μg/day, inhibited the growth ofPC-3 tumors more potently than reference peptide JMR-132. The inhibitoryeffect of Peptides 1109 and 11109 at the two dose levels was highlysignificant (p<0.01), while the effect of JMR-132 had a lowersignificance level (p<0.05) (Table IV.)

TABLE IV Experiment 2: Effect of Treatment with GH-RH Antagonists onPC-3 Human Prostate Cancer Xenografts in Nude Mice Tumor growthInhibition Significance Group after 2 weeks (%) (%) versus controlControl 716 JMR-132 (10 μg/day) 432 39.61 p < 0.05 Peptide 1109 (5μg/day) 311 56.58 p < 0.01 Peptide 11109 (5 μg/day) 217 69.68 p < 0.01Peptide 11109 (2 μg/day) 318 55.55 p < 0.01

Experiment 3:

All peptides of the present application, tested at the dose of 2 μg/day,more potently inhibited the growth of PC-3 tumors than the referencepeptide JMR-132 at a 5-fold dose of 10 μg/day. The inhibitory effect ofPeptide 11313, Peptide 11435, Peptide 11457, Peptide 11469, and Peptide11491 were statistically significant (p<0.01 and p<0.001). The effect ofreference peptide JMR-132 was not significant statistically. The resultsare shown in Table V.

TABLE V Experiment 3: Effect of Treatment with GH-RH Antagonists on PC-3Human Prostate Cancer Xenografts in Nude Mice Tumor growth Significanceinhibition versus Group after 4 weeks (%) control JMR-132 (10 μg/day)28.11 N.S. Peptide 11113 (2 μg/day) 29.37 N.S. Peptide 11119(2 μg/day)32.03 N.S. Peptide 11209 (2 μg/day) 48.04 N.S. Peptide 11313 (2 μg/day)78.20 p < 0.01 Peptide 11408 (2 μg/day) 63.61 N.S. Peptide 11435 (2μg/day) 75.11 p < 0.01 Peptide 11457 (2 μg/day) 85.98  p < 0.001 Peptide11459 (2 μg/day) 53.60 N.S. Peptide 11469 (2 μg/day) 78.07 p < 0.01Peptide 11491 (2 μg/day) 72.43 p < 0.01 N.S., not significant

Experiment 4:

After 28 days of treatment, all peptides of the present application,given at a dose of 2 μg/day, more potently inhibited the growth of PC-3tumors than the reference peptide JMR-132, which was administered at a5-fold higher dose of 10 μg/day. (Table VI). The inhibitory effects ofPeptide 11125, Peptide 11213, and Peptide 11473 were significant after28 days (Table VI).

TABLE VI Experiment 4: Effect of GH-RH Antagonists on PC-3 HumanProstate Cancer Xenografts in Nude Mice After 28 Days of Treatment Tumorgrowth Inhibition Significance Group after 28 days (%) (%) versuscontrol Control 1368 JMR-132 (10 μg/day) 1004 26.62 N.S. Peptide 11123(2 μg/day) 786 42.57 N.S. Peptide 11125 (2 μg/day) 424 68.97 p < 0.01Peptide 11213 (2 μg/day) 651 52.41 p < 0.05 Peptide 11433 (2 μg/day) 95630.15 N.S. Peptide 11473 (2 μg/day) 442 67.68 p < 0.01 Peptide 11485 (2μg/day) 794 41.96 N.S. Peptide 11497 (2 μg/day) 872 36.25 N.S. Peptide11499 (2 μg/day) 782 42.86 N.S. Peptide 11521 (2 μg/day) 877 35.86 N.S.N.S., not significant

At the end of experiment, after 46 days of treatment, Peptide 11125,Peptide 11213, Peptide 11473, Peptide 11485, and Peptide 11497 had amore potent inhibitory effect than reference peptide JMR-132 at a 5-folddose (Table VII). At the end of the experiment, the inhibitory effectsof Peptide 11125, Peptide 11213, Peptide 11473, and Peptide 11485 werestatistically significant. Reference peptide JMR-132 had no significantinhibitory effect at the end of experiment (Table VII).

TABLE VII Experiment 4: Effect of GH-RH Antagonists on PC-3 HumanProstate Cancer Xenografts in Nude Mice After 46 Days of Treatment Tumorgrowth Inhibition Significance Group after 46 days (%) (%) versuscontrol Control 3330 JMR-132 (10 μg/day) 1848 44.52 N.S. Peptide 11123(2 μg/day) 1849 44.48 N.S. Peptide 11125 (2 μg/day) 1009 69.69 p < 0.05Peptide 11213 (2 μg/day) 1144 65.65 p < 0.05 Peptide 11433 (2 μg/day)1890 43.23 N.S. Peptide 11473 (2 μg/day) 1072 67.80 p < 0.05 Peptide11485 (2 μg/day) 1257 62.24 p < 0.05 Peptide 11497 (2 μg/day) 1658 50.22N.S. Peptide 11499 (2 μg/day) 2178 34.59 N.S. Peptide 11521 (2 μg/day)2427 27.11 N.S. N.S., not significant

Example IX Effect of GH-RH Antagonists on H-460 Human Non-Small CellLung Cancer (Non-SCLC) Xenografts in Nude Mice

Experiment 1:

Male nude mice were implanted s.c. with 3 mm³ pieces of H-460 humannon-SCLC tumor tissue on both flanks. When tumors had grown to a meanvolume of approximately 90 mm³, the mice were randomly assigned into 4experimental groups with 10 animals in each group and received singledaily injections for 28 days as follows: 1. Control (vehicle solution);2. JMR-132 (10 μg/day s.c.); 3. Peptide 1109 (10 μg/day s.c.); 4.Peptide 11111 (10 μg/day s.c.). Tumor volumes were measured once a week.The experiment was ended on day 28 by sacrificing the mice underIsoflurane anesthesia. Resulting tumors were cleaned, weighed, andsnap-frozen until further analyses. Statistical analyses of themeasurement results were done by two-tailed t-test, p<0.05 beingconsidered significant. Data are presented as the means±S.E.

Experiment 2:

Male nude mice were implanted s.c. with 3 mm³ pieces of H-460 humannon-SCLC tumor tissue on both flanks. When tumors had grown to a meanvolume of approximately 90 mm³, the mice were randomly assigned into 12experimental groups with 8 to 10 animals in each group and receivedsingle daily injections for 28 days as follows: 1. Control (vehiclesolution); 2. JMR-132 (10 μg/day s.c.); 3. Peptide 11109 (5 μg/days.c.); 4. Peptide 11113 (5 μg/day s.c.); 5. Peptide 11119 (5 μg/days.c.); 6. Peptide 11209 (5 μg/day s.c.); 7. Peptide 11313 (5 μg/days.c.); 8. Peptide 11408 (5 μg/day s.c.); 9. Peptide 11435 (5 μg/days.c.); 10. Peptide 11459 (5 μg/day s.c.); 11. Peptide 11469 (5 μg/days.c.); 12. Peptide 11491 (5 μg/day s.c.). Tumor volumes were measuredonce a week. The experiment was ended on day 28 by sacrificing the miceunder Isoflurane anesthesia. Resulting tumors were cleaned, weighed, andsnap-frozen until further analyses. Statistical analyses of themeasurement results were done by two-tailed t-test, p<0.05 beingconsidered significant. Data are presented as the means±S.E.

Experiment 3:

Male nude mice were implanted s.c. with 3 mm³ pieces of H-460 humannon-SCLC tumor tissue on both flanks. When tumors had grown to a meanvolume of approximately 90 mm³, the mice were randomly assigned into 8experimental groups with 8 to 10 animals in each group and receivedsingle daily injections for 28 days as follows: 1. Control (vehiclesolution); 2. JMR-132 (10 μg/day s.c.); 3. Peptide 11123 (5 μg/days.c.); 4. Peptide 11125 (5 μg/day s.c.); 5. Peptide 11307 (5 μg/days.c.); 6. Peptide 11317 (5 μg/day s.c.); 7. Peptide 11473 (5 μg/days.c.); 8. Peptide 11485 (5 μg/day s.c.). Tumor volumes were measuredonce a week. The experiment was ended on day 28 by sacrificing the miceunder Isoflurane anesthesia. Resulting tumors were cleaned, weighed, andsnap-frozen until further analyses. Statistical analyses of themeasurement results were done by two-tailed t-test, p<0.05 beingconsidered significant.

Results

Experiment 1:

Among the GH-RH antagonists tested, Peptide 1109 and Peptide 11111exerted a significant inhibitory effect (p<0.01 and p<0.05,respectively) on the growth of H-460 tumors, while the effect ofreference peptide JMR-132 was not significant (Table VIII). Theantitumor effect of Peptide 1109 was also significantly higher (p<0.05)than that of the reference peptide JMR-132 (Table VIII).

TABLE VIII Experiment 1: Effect of Treatment with GH-RH Antagonists onH-460 Human non-SCLC Tumor Xenografts in Nude Mice Tumor growthSignificance Significance Group after 4 weeks (%) versus control versusJMR-132 Control 4434 ± 1099 JMR-132 2404 ± 604 0.081 (N.S.) Peptide 11091042 ± 181 0.004 0.042 Peptide 11111 2005 ± 541 0.035 0.824 N.S., notsignificant

Experiment 2:

All new peptides tested, with the exception ofPeptide 11109, inhibitedthe growth of H-460 lung cancers in vivo at a dose of 5 μg/day. Theinhibitory effects of Peptide 11459 and Peptide 11491 were statisticallysignificant (p<0.05). Peptide 11109 had no effect. Reference peptideJMR-132, even at a two-fold increased dose of 10 μg/day, had noinhibitory effect and in fact non-significantly stimulated the growth ofH-460 tumors (Table IX).

TABLE IX Experiment 2: Effect of Treatment with GH-RH Antagonists onH-460 Human non-SCLC Tumor Xenografts in Nude Mice Tumor growth after 4weeks Inhibition Significance Group (%) (%) versus control Control 7894± 2040 JMR-132 (10 μg/day) 11537 ± 8215  (−46.14) 0.4941 stimul. Peptide11109 (5 μg/day) 7890 ± 4127  0.05 0.6672 Peptide 11113 (5 μg/day) 6790± 3340 13.98 0.8533 Peptide 11119 (5 μg/day) 5254 ± 1524 33.44 0.6131Peptide 11209 (5 μg/day) 6377 ± 2477 19.21 0.9499 Peptide 11313 (5μg/day) 3091 ± 1215 60.84 0.0906 Peptide 11408 (5 μg/day) 3998 ± 111349.35 0.2042 Peptide 11435 (5 μg/day) 4170 ± 2064 47.17 0.4136 Peptide11459 (5 μg/day) 2418 ± 923  69.36 0.0297 Peptide 11469 (5 μg/day) 4810± 1977 39.06 0.5182 Peptide 11491 (5 μg/day) 1926 ± 473  75.60 0.0106N.S., not significant

Experiment 3:

Peptide 11123, Peptide 11125, Peptide 11307, Peptide 11317, and Peptide11473, tested at the dose of 5 μg/day, more potently inhibited thegrowth of H-460 lung tumors than the reference peptide JMR-132 at a2-fold higher dose of 10 μg/day. The inhibitory effect of Peptide 11473reached statistical significance (p<0.05) already after the first weekof treatment, and it remained significant throughout the experiment. Theresults are shown in Table X.

TABLE X Experiment 3: Effect of Treatment with GH-RH Antagonists onH-460 Human non-SCLC Tumor Xempgrafts in Nude Mice Tumor growthinhibition Group after 4 weeks (%) JMR-132 (10 μg/day) 15.37 Peptide11123 (5 μg/day) 35.74 Peptide 11125 (5 μg/day) 33.03 Peptide 11307 (5μg/day) 30.98 Peptide 11317 (5 μg/day) 41.00 Peptide 11473 (5 μg/day)54.64 Peptide 11485 (5 μg/day) 9.04

Example X Effect of GH-RH Antagonists on MDA-MB-231 Human EstrogenIndependent Breast Cancer Xenografts in Nude Mice

Female nude mice were xenografted s.c. with MDA-MB-231 tumor tissue fromdonor animals. When tumors had grown to a mean volume of approximately50 mm³, the mice were randomly assigned into 2 experimental groups with10 animals in each group and received single daily injections for 28days as follows: 1. Control (vehicle solution); 2. Peptide 1109 (5μg/day s.c.). Tumor volumes were measured once a week. The experimentwas ended on day 28 by sacrificing the mice under Isoflurane anesthesia.Resulting tumors were cleaned, weighed, and snap-frozen until furtheranalyses. Statistical analyses of the measurement results were done bytwo-tailed t-test, p<0.05 being considered significant.

Results

Peptide 1109 at a dose of 5 μg/day inhibited the growth of MDA-MB-231human breast cancers in nude mice by about 75%. The inhibitory effectbecame statistically significant (p<0.05) after 2 weeks of treatment andit remained significant (p<0.05) for the rest of the experiment.

Example XI Effect of GH-RH Antagonists on NCI-N87 Human Gastric CancerXenografts in Nude Mice

NCI-N87 cancers were transplanted s.c. into both flank areas of 30female nude mice. The mice were randomly assigned into 4 experimentalgroups with 6 to 9 animals in each group and received single dailyinjections for 77 days as follows: 1. Control (vehicle solution); 2.JMR-132 (10 μg/day s.c.); 3. Peptide 1109 (10 μg/day s.c.); 4. Peptide11479 (10 μg/day s.c.). Tumor volumes were measured once a week. Theexperiment was ended on day 77 by sacrificing the mice under Isofluraneanesthesia. Resulting tumors were cleaned, weighed, and snap-frozenuntil further analyses. Statistical analyses of the measurement resultswere done by two-tailed t-test, p<0.05 being considered significant.Data are presented as the means±S.E.

Results

Peptide 1109 and Peptide 11479 had significant inhibitory effect(p<0.05) on the growth of NCI-N87 cancers in nude mice. Moreover, 6 outof 11 tumors regressed in the group treated with Peptide 1109. Referenceantagonist JMR-132 was not effective. The results are shown in Table XI.

TABLE XI Effect of Treatment with GH-RH Antagonists on NCI-N87 HumanGastric Cancer Xenografts in Nude Mice Tumor Tumor Number of Number ofgrowth after Tumor weights doubling time tumors per regressing Group 77days (%) (mg) (days)† group tumors Control 442 ± 119 446 ± 147 42.0 ±5.9 12 1 JMR-132 409 ± 78 407 ± 175 40.8 ± 5.9 15 2 Peptide 1109 225 ±59* 170 ± 52  93.6 ± 30.7 11 6 Peptide 11479 235 ± 48* 144 ± 41  156.7 ±55.7* 14 1 *p < 0.05 vs. control. †Tumor doubling time was calculatedwithout the regressing tumors.

Example XII Effect of GH-RH Antagonists on Panc-1 Human CancerXenografts in Nude Mice

Panc-1 cancers were transplanted s.c. into both flank areas of 60 femalenude mice, and allowed to grow for 105 days before starting thetreatment with GH-RH antagonists. The mice were randomly assigned into 3experimental groups with 8 animals in each group and received singledaily injections for 36 days as follows: 1. Control (vehicle solution);2. JMR-132 (10 μg/day s.c.); 3. Peptide 11457 (10 μg/day s.c.). Tumorvolumes were measured once a week. The experiment was ended on day 82 bysacrificing the mice under Isoflurane anesthesia. Resulting tumors werecleaned, weighed, and snap-frozen until further analyses. Statisticalanalyses of the measurement results were done by two-tailed t-test,p<0.05 being considered significant. Data are presented as themeans±S.E.

Results

Peptide 11457 powerfully inhibited the growth of Panc-1 human pancreaticcancers in nude mice for at least 82 days although the treatment wasstopped after 36 days. Reference peptide JMR-132 was less effective. Theresults are shown in Table XII.

TABLE XII Effect of Treatment with GH-RH Antagonists on Panc-1 HumanPancreatic Cancer Xenografts in Nude Mice Tumor growth from Tumor volumeon Tumor weights Group day 1 to day 82 (%) day 82 (mm³) (mg) Control3190 ± 710 2040 ± 1357  606 ± 340 JMR-132 1730 ± 350 511 ± 221*  185 ±105* Peptide 11457   740 ± 1220* 262 ± 103*  76 ± 166* *p < 0.05 vs.control

Example XIII Effect of GH-RH Antagonists on SK-Hep-1 HumanHepatocellular Cancer Xenografts in Nude Mice

SK-Hep-1 cancers were transplanted s.c. into both flank areas of 66female nude mice, and allowed to grow for 47 days before starting thetreatment with GH-RH antagonists. The mice were randomly assigned into 4experimental groups with 8 animals in each group and received singledaily injections for 135 days as follows: 1. Control (vehicle solution);2. JMR-132 (10 μg/day s.c.); 3. Peptide 1109 (5 μg/day s.c.); 4. Peptide1109 (10 μg/day s.c.). Tumor volumes were measured once a week. Theexperiment was ended on day 135 by sacrificing the mice under Isofluraneanesthesia. Resulting tumors were cleaned, weighed, and snap-frozenuntil further analyses. Statistical analyses of the measurement resultswere done by two-tailed t-test, p<0.05 being considered significant.Data are presented as the means±S.E.

Results

Peptide 1109, even in a lower dose of 5 μg/day, more potently inhibitedthe growth of SK-Hep-1 hepatic cancers than the reference peptideJMR-132 at a dose of 10 μg/day. The inhibitory effect of JMR-132 was notsignificant, however the effect of Peptide 1109 at the 10 μg/day doselevel was statistically significant. In addition, Peptide 1109 causedtotal regression of 5 tumors out of 13 at a dose of 5 μg/day, and asmany as 7 out of 13 tumors regressed at the higher dose of 10 μg/day. Bycomparison, in the group treated with 10 μg/day of JMR-132, only 2tumors regressed out of 12. One tumor out of 10 also regressed in thecontrol group (spontaneous regression occasionally occurs in untreatedSK-Hep-1 cancers). The results are summarized in Table XIII.

TABLE XIII Effect of Treatment with GH-RH Antagonists on SK-Hep-1 HumanHepatocellular Cancer Xenografts in Nude Mice Tumor volume Number ofTumors with (mm³) on day Tumor weights† tumors per total Group 135 (mg)group regression Control 730 ± 434 1388 ± 843 (5) 10 1 JMR-132 (10μg/day) 615 ± 372 1006 ± 569 (7) 12 2 Peptide 1109 (5 μg/day) 271 ± 98 565 ± 115 (6) 13 5 Peptide 1109 (10 μg/day) 200 ± 123*  605 ± 281 (4)13 7 †The numbers in parentheses show the number of tumors removed atautopsy. *p = 0.030 vs control.

Example XIV PC3 Prostate Cancer Data—Including Data for P11604 andP11606

Male nude mice were implanted s.c. with 3 mm³ pieces of PC-3 humanhormone-independent prostate cancer tissue on both flanks. When tumorsreached a volume of approximately 50 mm³, the mice were divided into 8experimental groups with 8 to 10 animals in each group and receivedsingle daily injections for 28 days as follows: 1. Control (vehiclesolution); 2. P-11513 2 μg/day; 3. P-11602 2 μg/day; 4. P-11602 1μg/day; 5. P-11604 2 μg/day; 6. P-11606 2 μg/day; 7. P-11610 2 μg/day;8. P-11610 1 μg/day.

Tumor volumes were measured once a week. The experiment was ended on day28 by sacrificing the mice under Isoflurane anesthesia. Resulting tumorswere cleaned, weighed, and snap-frozen until further analyses.Statistical analyses of the measurement results were done by two-tailedt-test, p<0.05 being considered significant.

TABLE XIV Effect of new GHRH antagonists on PC3 androgen-independentprostate cancer 0 7 14 21 28 days TUMOR GROWTH (%) CONTROL 100 331.28590.95 1290.10 1857.23 P-11513 2 μg/day 100 212.49 420.81 823.51 1420.09P-11602 2 μg/day 100 197.77 270.61 449.82 641.31 P-11602 1 μg/day 100249.81 295.25 467.74 740.06 P-11604 2 μg/day 100 159.84 199.57 316.88383.97 P-11606 2 μg/day 100 145.65 307.66 521.69 709.50 P-11610 2 μg/day100 132.24 289.25 466.31 631.89 P-11610 1 μg/day 100 195.49 302.30549.94 740.17 TUMOR INHIBITION (%) P-11513 2 μg/day 35.86 28.79 30.8023.54 P-11602 2 μg/day 40.30 54.21 62.20 65.47 P-11602 1 μg/day 24.5950.04 60.70 60.15 P-11604 2 μg/day 51.75 66.23 73.37 79.33 P-11606 2μg/day 56.03 47.94 56.16 61.80 P-11610 2 μg/day 60.08 51.05 60.82 65.98P-11610 1 μg/day 40.99 48.84 53.79 60.15

Example XV Effects of New GHRH Antagonists on Human Non-Small Cell LungCancer Cell Line H460

The aim of this study was to find out the tumor inhibitor effect of thelatest GHRH antagonists (Peptide 11423, Peptide 11602, Peptide 11604,Peptide 11606) on H460 human non-small cell lung cancer cell line.Female nude mice were xenografted subcutaneously with approximately 3mm³ pieces of H460 human non-small cell lung cancer malignant tumortissue. When tumors reached the mean volume of approximately 90 mm³, theanimals was randomly assigned into different groups. Tumor volumes andbody weight were measured once a week. At the end of the experiment micewere anesthetized and sacrificed. Tumors were carefully excised, weighedand were stored at −80° C. until further investigation. Organs and tumorsamples were preserved in 10% formaldehyde.

TABLE XV # Group of mice Treatment Control 9 vehicle Peptide 11602 7daily sc.injections of peptide 11602 (5 μg/day) Peptide 11604 7 dailysc.injections of peptide 11604 (5 μg/day) Peptide 11606 7 dailysc.injections of peptide 11606 (5 μg/day) Peptide 11423 8 dailysc.injections of peptide 11423 (5 μg/day)

TABLE XVII Tumor Growth (%) day 1 day 7 day 14 day 21 day 28 Control100.00 529.86 1382.69 2469.01 4099.48 peptide 11423 5 μg/day 100.00412.37 761.10 1130.90 2687.38 peptide 11602 5 μg/day 100.00 247.89504.42 864.16 2575.35 peptide-11604 5 μg/day 100.00 341.87 609.381006.40 1595.34 peptide 11606 5 μg/day 100.00 221.26 494.68 933.191482.03

TABLE XVII Tumor inhibition (%) day 1 day 7 day 14 day 21 day 28 Controlpeptide11423 5 μg/day 22.17 44.95 54.20 34.45 peptide 11602 5 μg/day53.21 63.52 65.00 37.18 peptide-11604 5 μg/day 35.48 55.93 59.24 61.08peptide 11606 5 μg/day 58.24 64.22 62.20 63.85

Example XVI Protocol for HT Human Diffuse Mixed B Cell Lymphoma CellLine Experiment

The aim of this study was to find out the tumor inhibitor effect of thelatest GHRH antagonists (Peptide 11602, Peptide 11604, Peptide 11606,and Peptide 11610) at the dose of 5 μg/day on HT human diffuse mixed Bcell lymphoma cell line. Female nude mice were xenograftedsubcutaneously with approximately 3 mm³ pieces of HT malignant tumortissue. When tumors reached the mean volume of approximately 120 mm³,the animals were randomly assigned into different groups. Tumor volumesand body weight were measured once a week. At the end of the experimentmice were anesthetized and sacrificed. Tumors were carefully excised,weighed and were stored at −80° C. until further investigation. Organsand tumor samples were preserved in 10% formaldehyde.

TABLE XVII # Group of mice Treatment Control 7 vehicle Peptide 11602 7daily sc.injections of peptide 11602 (5 μg/day) Peptide 11604 7 dailysc.injections of peptide 11604 (5 μg/day) Peptide 11606 7 dailysc.injections of peptide 11606 (5 μg/day) Peptide 11610 7 dailysc.injections of peptide 11610 (5 μg/day)

TABLE XIX HT human diffuse mixed B cell lymphoma cell line Tumor volume(mm³) Tumor volume (mm³) day 1 day 7 day 14 day 21 day 28 Control 105.76217.86 413.23 544.84 1188.23 Peptide 11602 5 μg/day 194.81 260.13 311.76332.67 509.24 Peptide 11604 5 μg/day 125.04 165.21 231.44 563.86 818.2Peptide-11606 5 μg/day 128.49 223.02 341.77 510.24 716.13 Peptide 116105 μg/day 90.42 145.53 194.57 250.24 428.99

TABLE XX Tumor growth (%) day 1 day 7 day 14 day 21 day 28 Control 100305.66 482.84 781.55 896.53 P-11602 5 μg/day 100 192.86 281.4 462.45608.23 P-11604 5 μg/day 100 129.89 175.7 271.36 338.41 P-11606 5 μg/day100 209.74 352.2 453.71 660.24 P-11610 5 μg/day 100 183.36 307.98 361.18519.79

TABLE XXI Tumor inhibition (%) day 1 day 7 day 14 day 21 day 28 Controlpeptide 11602 5 μg/day 0 36.94 41.71 40.82 32.15 peptide 11604 5 μg/day0 57.53 63.61 65.27 62.25 peptide-11606 5 μg/day 0 31.38 27.05 41.9426.35 peptide 11610 5 μg/day 0 40.01 36.21 53.78 42.02

Example XVII Xenograft Ovarian Tumor Model of Ovarian Cancer Test

Human ovarian cancer SKOV3 cells growing exponentially were implantedinfo five female nude mice by subcutaneous (s.c.) injection of 10⁷ cellsin both flanks. Tumors That resulted after approximately 4 weeks indonor animals were then aseptically dissected and mechanically minced.Three mm³ pieces of tumor tissue were transplanted subcutaneously intoexperimental animals with a trocar needle. When tumors reached anappropriate size (approximately 50 mm³), mice were randomly divided intotwo groups. The first was the control group, the second group wastreated with daily s.c. injections of 5 μg P-11313, the third group wastreated with daily s.c. injections of 5 μg P-11604, the fourth group wastreated with daily s.c. injections of 5 μg P-11610. Tumor volume(length×width×height×0.5236) was measured every week and mean tumorvolumes of each group were compared by Student's t-test. The studylasted 49 days. One week after end of treatment, mice were killed underanesthesia, tumors were snap frozen and stored at −70° C.

Effects of P-11313, P-11604 and P-11610 on SKOV3 Ovarian CancerXenografts

day 0 day 7 day 14 day 21 day 28 day 35 day 42 day 49 TU growth (%)CONTROL 100 214.38 280.25 543.5 842 892.83 1236 1272 P-11313 5 μg/day100 147.84 140 196.6 249.65 201.5 274.05 328.63 P-11604 5 μg/day 100144.55 174.5 179.5 167.5 182.88 397.95 309.96 P-11610 5 μg/day 100137.44 150.1 239.14 204.07 242.05 273.83 383.93 TU inhibition (%)CONTROL P-11313 5 μg/day 31.04 50.04 63.83 70.35 77.43 77.83 74.16P-11604 5 μg/day 32.57 37.73 66.97 80.12 79.52 67.80 75.63 P-11610 5μg/day 35.89 46.44 56.00 75.76 72.89 77.85 69.82

What is claimed is:
 1. A method of treating a subject with cancercomprising administering a therapeutically effective amount of at leastone GHRH antagonist peptide of the formula:[A⁰-Tyr¹,D-Arg²,A⁴,A⁶,A⁸,Har⁹,Tyr(Me)¹⁰,A¹¹,A¹²,Abu¹⁵,A¹⁷,A²⁰,A²¹,Nle²⁷,D-Arg²⁸,A²⁹-A³⁰-A³¹]hGH-RH(1-29)NH₂wherein A⁰ is PhAc, N-Me-Aib, Dca, Ac-Ada, Fer, Ac-Amc, Me-NH-Sub,PhAc-Ada, Ac-Ada-D-Phe, Ac-Ada-Phe, Dca-Ada, Dca-Amc, Nac-Ada, Ada-Ada,or CH₃—(CH₂)₁₀—CO-Ada, A⁴ is Ala or Me-Ala, A⁶ is Cpa or Phe(F)₅, A⁸ isAla, Pal, or Me-Ala, A¹¹ is His or Arg, A¹² is Lys, Lys(0-11), Lys(Me)₂or Orn, A¹⁷ is Leu or Glu, A²⁰ is Har or His, A²¹ is -Lys, Lys(Me)₂ orOrn, A²⁹ is Har, Arg or Agm, A³⁰ is absent, β-Ala, Amc, Apa, Ada, AE₂A,AE₄P, ε-Lys(α-NH₂) or Agm, A³¹ is absent, Lys(Oct) or Ahx, provided thatwhere A⁰ is PhAc, A¹² and A²¹ are both other than Orn and A³⁰ is notabsent and is not Agm, and pharmaceutically acceptable salts thereof. 2.The method of claim 1, wherein the GHRH antagonist peptide is selectedfrom the group consisting of: P-11107 [(N-Me-Aib)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11109 [Dca⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂;P-11111 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11113 [Fer⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11115 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11117 [(PhAc-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11119 [(Ac-Ada-D-Phe)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11121 [(Ac-Ada-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11123 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11125 [(CH₃—(CH₂)₁₀—CO-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, P-11207 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂; P-11209 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Apa³⁰]hGH-RH(1-29)NH₂; P-11211 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11215 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11307 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂; P-11309 [(Me-NH-Sub)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂; P-11311 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Agm²⁹]hGH-RH(1-29); P-11313 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Agm³⁰]hGH-RH(1-29); P-11315 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11317 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11321 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11407 [(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11408 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11409 [(Ac-Amc)⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11411 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂; P-11415 [(Ac-Amco)⁰-Tyr¹, D-Arg², Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Agm³⁰]hGH-RH(1-29); P-11417 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂; P-11421 [(N-Me-Aibo)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂; P-11427 [(N-Me-Aib)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0-11)¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ wherein (0-11) isN-Me-Aib-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His- and theC-terminal carbonyl group of the (0-11) peptide sequence forms an amidebond with the epsilon amino group of Lys¹²; P-11431 [(N-Me-Aib)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂; P-11435[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11437[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11439[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵,His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11441[(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,(Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11443 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11445 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, (Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11449 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Har²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11451 [(Nac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, D-Arg²⁸,Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂; P-11453 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, D-Arg²⁸,Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂; P-11455 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂; P-11459 [(PhAc-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11461 [(Ac-Ada-Phe)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11463 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂; P-11465 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11467 [(Ada-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11469 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11471 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0-11)¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ wherein (0-11) isPhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His- and theC-terminal carbonyl group of the (0-11) peptide sequence forms an amidebond with the epsilon amino group of Lys¹²; P-11473 [(PhAc-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11475[(Ac-Ada-D-Phe)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂;P-11477 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, Glu¹⁷, His²⁰, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂;P-11479 [(Ac-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11481 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-ε-Lys(α-NH₂)³⁰-Ahx³¹]hGH-RH(1-29)NH₂; P-11483 [(Ac-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂; P-11485[(CH₃—(CH₂)₁₀CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂;P-11487 [(CH₃—(CH₂)₁₀CO-Ada)⁰-Tyr, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Omr¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11491 [(Dca-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11497 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰hGH-RH(1-29)NH₂; P-11501 [(Ac-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂; P-11503[(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹²,Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂; P-11513 [Dca⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Har²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11515 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0-11)¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ wherein (0-11) isPhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His- and theC-terminal carbonyl group of the (0-11) peptide sequence forms an amidebond with the epsilon amino group of Lys¹²; P-11601[(CH₃—(CH₂)₁₀—CO-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11602 [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11603 [(Dca-Ada)⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂; P-11604 [(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹, Agm³⁰]hGH-RH(1-29); P-11606 [(PhAc-Ada)⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹, Agm³⁰]hGH-RH(1-29); P-11611[(Ac-Amc)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂;P-11612 [(Ac-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11620 [(Ac-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Arg²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11621 [(Me-NH-Sub)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11629 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,(Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂; P-11701 [(Dca-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Glu¹⁷, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂; P-11702 [(Dca-Ada)⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Glu¹⁷, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂; P-11703 [(Dca-Ada)⁰-Tyr¹,D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Glu¹⁷, Har²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂; P-11704[(CH₃—(CH₂)₁₀—CO-Ada)⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹,Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-AE₄P³⁰]hGH-RH(1-29)NH₂, and combination thereof.
 3. The method ofclaim 1, wherein the cancer is selected from lung cancer, prostatecancer, breast cancer, ovarian cancer, endometrial cancer, gastriccancer, intestinal cancer, pancreatic cancer, kidney cancer, bonecancer, liver cancer, glioblastomas, pheochromocytomas, melanomas, andlymphomas.
 4. The method of claim 1, wherein the administration of theat least one GHRH antagonist peptide is selected from the groupconsisting of subcutaneous, intramuscular, transdermal and intravenousinjection.
 5. The method of claim 1, wherein the at least one GHRHantagonist peptide is administered at a dose in the range of 2 to 20milligrams/day/subject.
 6. The method of claim 1, wherein the at leastone GHRH antagonist peptide is selected from: P-11602 [(PhAc-Ada)⁰-Tyr¹,D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂; P-11604 [(PhAc-Ada)⁰-Tyr¹,D-Arg², (Phe(F)₅)⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰,Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹, Agm³⁰]hGH-RH(1-29); P-11606[(PhAc-Ada)⁰-Tyr¹, D-Arg², (Phe(F)₅)⁶, (Me-Ala)⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸, Har²⁹,Agm³⁰]hGH-RH(1-29), and combination thereof.
 7. A method of treating asubject with cancer comprising administering a therapeutically effectiveamount of at least one GHRH antagonist peptide selected from the groupconsisting of: P-11419 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰,His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂; P-11429 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-(β-Ala³⁰-Lys(Oct)³¹]hGH-RH(1-29)NH₂; P-11457 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11499 [PhAc⁰-Tyr¹, D-Arg²,(Phe(F)₅)⁶, Ala, Har⁹, Tyr(Me)¹⁰, His, Orn¹², Abu⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-1109 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, Glu¹⁷, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, P-1111 [PhAc⁰-Tyr¹, D-Arg², (Me-Ala)⁴, Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, P-1113 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, (Me-Ala)⁸,Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, P-1115 [PhAc⁰-Tyr¹, Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷, D-Arg²⁸,Har²⁹]hGH-RH(1-29)NH₂, P-1117 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸, Har⁹,Tyr(Me)¹⁰, His¹¹, (Lys(Me)₂)¹², Abu¹⁵, His²⁰, (Lys(Me)₂)²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, P-11213 [Oct⁰-Tyr¹, D-Arg², Cpa⁶, Ala⁸,His⁹, Tyr(Et)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷, D-Arg²⁸,Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, P-11319 [(Ac-Ada)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, His⁹, Tyr(Et)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, P-11423 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶,Dip⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, P-11425 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Lys(0-11)¹², Abu¹⁵, His²⁰, Orn²¹,Nle²⁷, D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂ wherein (0-11) isPhAc-Tyr-D-Arg-Asp-Ala-Ilelle-Cpa-Thr-Ala-Har-Tyr(Me)-His- and theC-terminal carbonyl group of the (0-11) peptide sequence forms an amidebond with the epsilon amino group of Lys¹², P-11433 [Nac⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-AE₂A³⁰]hGH-RH(1-29)NH₂, P-11447 [PhAc⁰-Tyr¹, D-Arg²,Cpa⁶, Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Abu¹⁵, Har²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹]hGH-RH(1-29)NH₂, P-11521 [(Dca-Amc)⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Orn¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, P-11523 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His, Orn¹², Orn¹⁵, Glu¹⁷, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂, P-11525 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶,Ala⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Orn¹², Orn¹⁵, His²⁰, Orn²¹, Nle²⁷,D-Arg²⁸, Har²⁹-Ada³⁰]hGH-RH(1-29)NH₂; P-11413 [PhAc⁰-Tyr¹, D-Arg², Cpa⁶,3-Pal⁸, Har⁹, Tyr(Me)¹⁰, His¹¹, Abu¹⁵, His²⁰, Nle²⁷, D-Arg²⁸,Har²⁹-Amc³⁰]hGH-RH(1-29)NH₂, and combinations thereof.
 8. The method ofclaim 7, wherein the cancer is selected from lung cancer, prostatecancer, breast cancer, ovarian cancer, endometrial cancer, gastriccancer, intestinal cancer, pancreatic cancer, kidney cancer, bonecancer, liver cancer, glioblastomas, pheochromocytomas, melanomas, andlymphomas.
 9. The method of claim 7, wherein the administration of theat least one GHRH antagonist peptide is selected from the groupconsisting of subcutaneous, intramuscular, transdermal and intravenousinjection.
 10. The method of claim 7, wherein the at least one GHRHantagonist peptide is administered at a dose in the range of 2 to 20milligrams/day/subject.